PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of molcancBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleMolecular CancerJournal Front Page
 
Mol Cancer. 2010; 9: 144.
Published online 2010 June 11. doi:  10.1186/1476-4598-9-144
PMCID: PMC2906469

Glycogen synthase kinase 3 beta: can it be a target for oral cancer

Abstract

Despite progress in treatment approaches for oral cancer, there has been only modest improvement in patient outcomes in the past three decades. The frequent treatment failure is due to the failure to control tumor recurrence and metastasis. These failures suggest that new targets should be identified to reverse oral epithelial dysplastic lesions. Recent developments suggest an active role of glycogen synthase kinase 3 beta (GSK3 β) in various human cancers either as a tumor suppressor or as a tumor promoter. GSK3β is a Ser/Thr protein kinase, and there is emerging evidence that it is a tumor suppressor in oral cancer. The evidence suggests a link between key players in oral cancer that control transcription, accelerated cell cycle progression, activation of invasion/metastasis and anti-apoptosis, and regulation of these factors by GSK3β. Moreover, the major upstream kinases of GSK3β and their oncogenic activation by several etiological agents of oral cancer support this hypothesis. In spite of all this evidence, a detailed analysis of the role of GSK3β in oral cancer and of its therapeutic potential has yet to be conducted by the scientific community. The focus of this review is to discuss the multitude of roles of GSK3β, its possible role in controlling different oncogenic events and how it can be targeted in oral cancer.

Introduction

Oral cancer is the sixth most common cancer in the world, and its incidence varies in different ecogeographic regions [1,2]. Its occurrence is associated with exposure to smoking and alcohol consumption in the Western population. The majority of cases occur in Asia, where it is mainly associated with betel quid chewing [3]. Poor oral hygiene and human papillomavirus (HPV) infection of oral epithelial cells are other etiological factors [4]. In addition to genetic differences, other etiological factors promote the occurrence of this disease to different extents in different populations. Although there are several differences in disease occurrence and etiology between populations, there is one aspect of these tumors that is highly similar worldwide. Oral tumors are mainly asymptomatic initially, are aggressive, and frequently invade and migrate to distant organs, making them difficult to treat. This suggests that, although different predisposing factors activate various molecular pathways [5], eventually all of them may follow a common path thereafter to result in oral cancer.

Advances in recent decades in the surgical, radiotherapeutic and chemotherapeutic treatment of oral cancer have only modestly improved patient survival. Various approaches have been used for the clinical treatment of oral cancer patients in the last three decades, from non-targeted chemotherapy to highly targeted pharmacological inhibitors and specific monoclonal antibodies [3,6]. Although targeted therapies yield better outcomes than non-targeted therapies, frequent treatment failure suggests the need for new treatments or targets for this disease. In oral cancer, active transcription of various genes leads to rapid cell division, faster invasion and reduction of cell death. Although it has been largely overlooked, there is a potential link between key players in oral cancer, including transcription factors, cell cycle regulators, invasion/metastasis-promoting factors, and cell survival regulators, and their regulation under the control of glycogen synthase kinase 3β (GSK3β).

GSK3β plays a major role in epithelial cell homeostasis [7]. Its activity is regulated by site-specific phosphorylation of Tyr216/Ser9 residues [8]. The regulated phosphorylation of Ser9GSK3β is the main cause of various pathological conditions, and it is upregulated in epithelial cancers. Many upstream kinases protein kinase A (PKA) [9], Akt/PKB [10], PKC [11], p90 ribosomal S6 kinase/MAPK-activating protein (p90RSK/MAPKAP) [12] and p70 ribosomal S6 kinase (p70S6K) [13] are known to phosphorylate Ser9 of GSK3β, depending on the cellular context and various upstream regulators. The oncogenic activation of these upstream signaling molecules is frequently reported in oral squamous cell carcinoma (OSCC) [14-16]. Many of these oncogenic pathways are activated by common etiological factors of this cancer. Overall, this evidence suggests the possible active involvement of GSK3β-mediated signaling in this neoplastic disease. This review attempts to correlate the established pathways of oral cancer with GSK3β signaling and discusses the potential of this kinase as a therapeutic target.

The GSK3 family and its regulation

GSK3 was discovered nearly three decades ago in rabbit skeletal muscle as a protein kinase that phosphorylates and inactivates glycogen synthase, the final enzyme of glycogen biosynthesis [17,18]. GSK3 is a multifunctional Ser/Thr kinase with diverse roles in various human diseases, including diabetes, inflammation, neurological disorders and various neoplastic diseases [19,20]. To date, two members of the mammalian GSK3 family (α and β) are known [18]. They are ubiquitously expressed and highly conserved and are members of the CMGC family of protein kinases [21]. Many of the substrates of GSK3 need a "priming phosphate" (which is a Ser/Thr residue) located four amino acids (aa) C-terminally from the site of phosphorylation [8]. GSK3 is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals. Physiological regulation of GSK3 activity by various upstream kinases [9-13] in different physiological and pathological condition is established [8].

GSK3β and its role in tumorigenesis

GSK3β drives oncogenic progression either by its inhibition or its activation, depending on the cell type. In recent years, its role in cancer has become firmly established. The differences in the roles of GSK3β depending on the type of cancer are quite interesting. Whereas it has a growth-promoting role in some cancers, it suppresses growth in others. Based on the literature, it is clear that GSK3β can act either as a tumor promoter or as a tumor suppressor, as shown in Table Table11.

Table 1
Paradoxical role of GSK3β in various human cancers

GSK3β and its control over transcription

Alteration of the transcriptional machinery is common in neoplastic diseases, including oral cancer [22,23]. Oncogenic transcription factors (OTFs) alter the transcriptional machinery to regulate mRNA synthesis. GSK3β regulates the stability of various oncogenic TFs like the activator protein 1 (AP-1) [24], nuclear factor kappa B (NFκB) [25], c-Myc [26], β-catenin [27], Snail [28], Forkhead (FH) [29], CAAT-enhancer binding protein (C/EBPs) [30], and cAMP response element-binding (CREB) [31] by phosphorylation [8]. Most of these TFs are physiological targets of GSK3β that undergo proteasomal degradation upon phosphorylation [8,24-28]. AP-1 transcriptional activity is high in oral cancer tissue samples [2]. Active GSK3β directly phosphorylates c-Jun at Thr239 which promotes its degradation [24]. It is also known that in normal oral mucosa c-Jun is localized in the cytoplasm while it enters to the nucleus at the onset of oral carcinogenesis [32]. Both Fos and Jun are phosphorylated and activated by mitogen activated protein kinase (MAPK) and c-Jun n-terminal kinase (JNK) kinase system [33,34] may be due to inactive GSK3β. Moreover the expressions of p65 (one of the NFκB family member) have been observed in oral cancer tissue samples [35,36] and metastatic OSCC [36]. GSK3β phosphorylates p65 at Ser468 and negatively regulate its activity by promoting its degradation [25]. p65 might escape from its turnover because of inactivated GSK3β in OSCC. Recent report suggests active GSK3β physically interact with IκBα in normal epithelial cells [37]. Moreover study in different system suggests that active GSK3β blocks NFκB dependent transcription, by preventing IκBα degradation [38]. In normal epithelial cells NFκB activity is known to be inhibited by GSK3 [39]. From all these evidences, it seems like NFκB activation in OSCC may be modulated, because of inactive GSK3β like that in other epithelial cancers [40]. On the other hand, degradation of c-Myc and β-catenin is initiated by phosphorylation of GSK3β [26]. The overexpression of c-Myc and β-catenin protein in OSCC is established [41-46]. The gene mutation on hot spots i.e. Thr58 of c-Myc and Ser33, Ser37, Thr41 and Ser45 of β-catenin abolishes phosphorylation by GSK3β results in preventing ubiquitination and proteasome mediated degradation of c-Myc [47-50]/β-catenin [46,51-53] has been reported in various cancers but not so far in OSCC. In OSCC, c-Myc/β-catenin protein might get stability not because of missense mutation at these hot spot codons but because of inactivation of its phosphorylating kinase i.e. GSK3β it self. The activated Snail has been reported in OSCC [54]. GSK3β is well known regulator of Snail which phosphorylates and that leads to Snail nuclear export and deregulation [28,39,55,56]. Moreover, p53 is highly involved in OSCC [57]. Though it is inactivated by mutation in nearly half of oral cancer population [57] the cause of its inactivation is still doubtful in the other half. p53 activity is regulated by active GSK3β, due to either physical association or phosphorylation and post-translational modification [58,59]. It is possible that in OSCC cases without p53 mutations [57], p53 can be inactivated due to inactive GSK3β. These OTFs those are important in OSCC and are directly regulated possibly by GSK3β. Alteration of these TFs plays a vital role in various diseases, including OSCC.

GSK3β is a key player in OSCC

GSK3β can promote or suppress growth in different types of cancer (Table (Table1).1). The inactivation of GSK3β has been reported in most cancers of epithelial origin, such as skin, breast, and in cancers of the oral cavity, salivary glands, larynx, and esophagus [60]. The basal level of inactivated GSK3β (pSer9GSK3β) in OSCC cell lines is very high [61-63] but can be decreased by inhibiting the GSK3β upstream inactivating pathway [61,62]. A recent report suggests that activating GSK3β can reverse the epithelial-mesenchymal process in oral cancer [64]. GSK3β-mediated signaling could explain numerous molecular disorders specific to oral cancer.

A) Cell cycle regulation

Cell division is a precisely regulated process that occurs obligatorily in all organisms. The ability of cells to divide is mainly attributed to the presence of three classes of molecules: CDKs (Cyclin Dependent Kinases, a family of Ser/Thr kinases), their binding partners cyclins and CDK inhibitors (CDKI) [65]. The transcriptional and post-translational regulation of cyclin D1 [66,67] and of cyclin E [68,69] in OSCC are well documented. Cyclin D1/E transcriptional upregulation is achieved by regulating TFs (e.g., AP-1, NFκB, β-catenin), and protein stability/nuclear accumulation are also increased [70,71] in OSCC [66,68,69]. Inactive GSK3β prevents the phosphorylation of Thr286 cyclin D1 and Ser380 cyclin E, which blocks their nuclear export and degradation [70-72]. An inverse correlation between cyclin D1 and GSK3β expression has been reported in oral cancer [73]. Cyclin A and cyclin B are also overexpressed in OSCC [69,74,75]. These cyclins are primarily regulated by c-Myc and p53 and thus qualify as GSK3β targets. Because these are S phase- and G2-M phase-specific cyclins, their expression is affected by the G1 phase-specific cell cycle events of cyclin D1/CDK4 and cyclin E/CDK2 activation [57,76]. Overexpression of CDK4 mRNA has been reported in different malignancies, including oral and epithelial cancer [77,78]. c-Myc controls the expression of CDK4 by binding to E-box elements present in its promoter that are not only overexpressed in OSCC [42] but also are regulated by GSK3β [26]. p21 (WAF1/CIP1) competes with cyclins for binding to CDKs, and its expression is usually decreased in various cancers. However, in OSCC, the overexpression of p21 (WAF1/CIP1) is quite evident [79], and its overexpression significantly correlates with tumor size, lymph node involvement and clinical stage [79,80]. Active GSK3β directly regulates p21 expression by phosphorylation at Thr57 [81], leading to proteasome-mediated degradation. Another explanation could be that the TFs C/EBPα and -β (which may also be stabilized because of inactive GSK3β in OSCC) interact with p21 and protect it from degradation. The possible explanations for why p21 does not halt OSCC progression are numerous. One possible explanation is that p21 is inactivated by binding to the E7 protein of human papillomavirus 16 (HPV16), which is highly prevalent in OSCC. This association of p21 and E7 blocks the ability of p21 to inhibit cyclin/CDK activity as well as PCNA-dependent DNA synthesis. In contrast, another CDKI, p27, is reportedly down-regulated in OSCC [82] in a process that might be mediated by forkhead (FH) TF [29,83]. In breast cancer (where active GSK3β acts like a tumor suppressor as in OSCC; Table Table1)1) knock down of PI3K promotes degradation of FH and p27 possibly via GSK3β activation [84]. GADD45 and GADD153 are checkpoint inhibitors and tumor suppressors that have roles in multiple tumor types, including OSCC [85,86]. GADD45 is also controlled by p53, and upon DNA damage, it is activated to arrest the cell cycle. Both GADD45 and GADD153 are downstream targets of c-Myc [87] and thus qualify as possible GSK3β targets in OSCC. Cell division cycle 25A (CDC25A) is also controlled by c-Myc [69,76]. Direct evidence suggests a positive correlation between pSer9GSK3β and CDC25A expression in tumors of the oral cavity, salivary glands and larynx (Ref. [88] and Fig Fig11).

Figure 1
Progressive inactivation of GSK3β may promote accelerated cell cycle and oral cancer. As discussed in the text, most of the cell cycle regulators and their gain of function may be because of inactivation of GSK3β in oral cancer. GSK3β ...

B) Nodal invasion by epithelial-mesenchymal transition

OSCC is a cancer of epithelial cells that invades surrounding tissues and frequently migrates to distant organs (metastasizes) [89]. The extra cellular matrix (ECM) interaction is important for the survival of normal epithelial cells but this interaction is gradually lost in squamous cell carcinoma [90]. The major ECM molecules implicated in OSCC development include collagen, fibronectin [91], tenascin [92] and laminin [54,91,93]. Many ECM molecules are indirect targets of GSK3β via Snail- or AP-1 [28,94]. The degradation of basement membrane (collagen) by MMPs and its regulation by inactive GSK3β have been reported [95,96]. Focal adhesion kinase (FAK) is overexpressed in preinvasive and invasive OSCC [97]. Upregulation of FAK leads to migration, and its regulation by active NFκB is known in tongue squamous cell carcinoma cells (SCC25) [98,99] possibly via inactive GSK3β. Another group of molecules, the integrins, are transmembrane, heterodimeric, cell-surface proteins (consisting of one α and one β subunit) that primarily function as cell adhesion molecules but also participate in signal transduction leading to cell migration, growth and oncogenesis. Human integrins are upregulated in OSCC [100,101], and they are primarily controlled by those transcription factors regulated by GSK3β [102-104]. Recent evidence suggests a role for Snail in controlling multiple α/β-integrins and EMT in OSCC [54,94,105].

MMPs are a group of extracellular matrix/basement-degrading proteases. High levels of MMP-2, -3, and -9 have been associated with poor prognosis for patients with oral cancer, including the development of lymph node metastasis and poor survival [100,106,107]. The transcriptional activation of MMP-1,-3, and -9 is common in OSCC [108,109], and they are all targets of AP-1, NFκB, C/EBPs or Snail, highlighting the importance of GSK3β-mediated signaling in the oral cancer invasion program [110-112].

Cadherins interact with the actin cytoskeleton to maintain tissue architecture. In some cancers, including OSCC, loss of E-cadherin favors invasion. An inverse correlation between E-cadherin and Snail expression has been reported in OSCC and epithelial cancers [113-115], which supports the regulation of E-cadherin by the inactivation of GSK3β and Snail [28,64]. Snail represses E-cadherin gene expression in epithelial tumours [116]. GSK3β is well known regulator of Snail which phosphorylates and that leads to Snail nuclear export and deregulation [28,39,55,56]. Recent findings suggest that the forced activation of GSK3β and the resultant phosphorylation and cytoplasmic translocation of Snail lead to E-cadherin up-regulation, which can potentially reverse EMT in OSCC [64]. Yang et al. have shown that EMT phenotypes can be decreased in head and neck SCC (HNSCC) by the use of siRNA-mediated repression of Snail or by the use of inhibitors of PI3K, which is a GSK3β-inactivating upstream kinase [90]. On the other hand, elevated Cox-2 levels have been reported in various human malignancies, including OSCC [117-119]. Inhibition of Cox-2 decreases integrin and MMP levels as well as the invasiveness of OSCC [118,119]. Cox-2 gene transcription is controlled by wild-type p53 protein [120] and by NFκB in betel quid-associated oral cancer [121], indirectly supporting the importance of inactive GSK3β (Ref [122] and Fig Fig22).

Figure 2
Progressive inactivation of GSK3β may promote enhanced EMT and oral cancer. GSK3β regulates several molecules that participate in epithelial-mesenchymal transformation, invasion and metastasis in cancer. Normal epithelial cells are connected ...

C) Anti-Apoptosis

The inhibition of apoptosis is a major cause of neoplastic disorders and an integral part of oral cancer pathogenesis. Abundant evidence suggests a possible role for active GSK3β in cell survival and apoptosis [123,124]. Apoptosis is controlled by either the intrinsic (mitochondrial) or extrinsic pathway (activation of procaspase-8) [123,125-128].

Higher levels of Bcl-2 and lower levels of Bax are frequently reported in oral cancer [127]. A recent report suggests that, in an OSCC cell line, Bcl-2 expression is affected even by slight changes in the status of pSer9GSK3β [63]. Active GSK3β blocks CREB-dependent expression of the anti-apoptotic protein Bcl-2 [128]. Additionally, active GSK3β regulates p53 activity, which increases Bax protein levels to initiate apoptosis [125]. Modulation of GSK3β can markedly increase p53-dependent activation of Bax, leading to cytochrome c release, loss of mitochondrial membrane potential and caspase-9 processing [125]. Moreover, the physiological effect of p53 is governed by inactivation of GSK3β (pSer9 GSK3β) [125] (and not by pTyr216GSK3β). Inhibition of Akt (a well-known kinase upstream of GSK3β) can only induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -mediated apoptosis by regulating the levels of Bcl-2 and Bax in OSCC [125]. All of this evidence suggests that the survival advantage of OSCC cells over the normal oral epithelium might be due to progressive inactivation of GSK3β, which could be responsible for an increased Bcl-2/Bax protein ratio [63,125-127].

On the other hand, oral cancer cells are resistant to cell death mediated by TRAIL [126], which can be achieved only by inactivation of the GSK3-inactivating PI3K/Akt pathway [127]. Additionally, inhibition of caspase-8 reduces PI3K inhibitor-mediated apoptosis in OSCC [127]. In the extrinsic apoptotic pathway, active GSK3β promotes the activation of the initiator caspase-8 [122]. Therefore, active GSK3β targets both intrinsic and extrinsic pathways to maintain control over growth and proliferation in normal epithelium by promoting apoptosis [Fig. [Fig.3].3]. This control might be disrupted in OSCC.

Figure 3
Progressive inactivation of GSK3β may promote increased anti-apoptosis and oral cancer. GSK3β-mediated signaling controls apoptosis in OSCC. In the intrinsic apoptotic pathway, inactive GSK3β fails to promote apoptosis by the disruption ...

Oral cancer therapy and role of GSK3β signaling

The inhibition of GSK3β is regulated by various upstream kinases (PKA, PKB/Akt, PKC, p90RSK/MAPKAP, p70RS6K) [7,9,10,12,13,129]. PKA is predominantly controlled by extracellular signals (epidermal growth factor: EGF, platelet derived growth factor: PDGF), carcinogens and second messengers, mainly c-AMP. PKA activation in an OSCC cell line has been reported [63]. PKA-anchoring protein 220 (PKAP220) binds to both PKA and GSK3, bringing GSK3 into close proximity with PKA, which phosphorylates GSK3β to block its activity [130]. Recently, PKA has been identified as a therapeutic target in HNSCC; moreover, inhibition of PKA is known to affect many molecules (e.g., NFκB, Cyclin D1, Bcl-2, Cox-2 and p21), most of which are direct/indirect targets of GSK3β [131]. On the other hand, the activation of the PI3K/Akt pathway has been well studied in OSCC [15,127,132]. Direct evidence suggests that the pSer9GSK3β level in OSCC cell line is very high and can be decreased by inhibiting Akt signaling [62]. In addition, in oral cancer cells, blocking PI3K/Akt signaling causes more cells to undergo apoptosis; this effect is reversed by the use of a GSK3β inhibitor [63]. Akt signaling is important in HNSCC and is considered as a potential therapeutic target [133]. There is also evidence of PKC signaling in OSCC [11], and inhibition of PKC by pharmacological inhibitors reduces MMP-2 and MMP-9 [134], possibly via GSK3β. Suppression of PKC activity promotes GSK3β activity in epithelial cells, which increases apoptosis [7]. Targeting of PKCε has shown promising results in decreasing the invasion and mortality of HNSCC [135]. Moreover, p90RSK is known for its role in epithelial cell motility and invasiveness [136]. Tumor-promoting phorbol esters inhibit GSK3β via a classical MAPK cascade [19] by activating p90RSK (MAPKAP-KI). Therefore, the role of the p90RSK/GSK3β pathway might be important in oral cancer. Finally, GSK3β is inactivated by the mammalian target of rapamycin (mTOR) pathway, in which p70S6K phosphorylates GSK3β. In a SCC cell line, EGF inactivates GSK3β [137], which can be reversed by rapamycin at a concentration that blocks the activation of p70S6K [138]. Epidermal growth factor receptor (EGFR) activation in OSCC [137] might activate the p70S6K pathway [138]. Moreover, in HNSCC, p70S6K is reportedly very active, and targeting it with rapamycin has a potential anti-tumor effect in vivo [139], possibly due to the activation of GSK3β. All of these signaling pathways may have definite oncogenic properties and are activated by a variety of carcinogens or other cancer-promoting factors to induce oral cancer or cancers of similar epithelial origin. However, one thing that these oncogenic pathways share is that they all impinge on GSK3β inactivation. This may be the reason why, beyond geographical boundaries, all oral cancers are similar in their aggressiveness and their potential for migration and metastasis. Crosstalk is abundant in signal transduction pathways. Therefore, although targeting each of these pathways has a modest impact on oral cancer and causes toxicity to the patient, targeting GSK3β directly may be highly beneficial in treating OSCC [Fig. [Fig.44].

Figure 4
Targeting GSK3β pathway may be highly beneficial for curing oral cancer. Inhibition of GSK3β activity by the activation of several oncogenic pathways in cancer as discussed in the text. Activation of these pathways by several oral cancer ...

Oral cancer etiology and intracellular signaling

The activation of established GSK3-inactivating upstream biological pathways by oral cancer-predisposing factors, such as tobacco, alcohol, and HPV, support the proposition of a causative role for GSK3β in OSCC. The role of carcinogens (from chewing and smoking tobacco) in oral cancer is firmly established [15,140]. Smokers show elevated levels of adenyle cyclase (AC) and PKA activity in oral epithelial cells [141,142]. Chewing areca nuts can lead to DNA damage and increased oxidative stress. The lime (calcium hydroxide) that coats the betel leaf promotes an alkaline oral environment, which activates Akt signaling [15]. There is accumulating evidence that connects nicotine-induced tumorigenesis to the activation of MAPK signaling [143], activation of PI3K/Akt signaling [144] and blocking of cytochrome c-mediated apoptosis [145]. Alcohol abuse increases the permeability of cells to carcinogens and activates PKA in cell culture [146]. HPV activates Akt in epithelial keratinocytes [4,147]. Moreover, a recent evaluation of epithelial tumors suggests that HPV infection can alter many biological pathways to maintain malignant processes by decreasing focal adhesion and up-regulating Wnt signaling and cell cycle genes [148]. Therefore, it is logical to hypothesize that the inactivation of GSK3β contributes to oral cancer.

Evaluation of therapeutic potential and possible methods of targeting GSK3β in OSCC

Before selecting GSK3β as a therapeutic target in OSCC, its biological functions should be explored in detail. Though GSK3β has several isoforms, the isoform(s) specifically expressed in OSCC remain to be identified. If multiple isoforms are expressed, it will be important to understand their respective functions in oral cancer pathogenesis. The upstream cause of activation or inactivation of GSK3β as well as downstream target molecules and their status in OSCC should be thoroughly investigated at the patient level. Because it is an enzyme involved in regulating growth, cell cycle progression, apoptosis, and invasion, GSK3β may qualify as an ideal therapeutic target [123,149] for OSCC. Because of its role in both extrinsic and intrinsic apoptotic pathways, and because active GSK3β is nontoxic to non-cancerous cells (e.g., in a knock-in mouse study replacing Ser9 of GSK3β with Ala) [150], targeting the GSK3β pathway might be helpful in reducing unwanted apoptosis (in normal cells) and increasing useful apoptosis (in cancer cells).

The activation status of upstream molecules and the inactivation of GSK3β should be tested in different patients because each patient has a different lifestyle, etiological factors and genetic abnormalities. GSK3β can be inactivated by different upstream molecules in different oral tumors, even in the same patient. Inhibiting the upstream molecules pharmacologically by using peptide competitors and blocking phosphorylation at Ser9 certainly will keep GSK3β in an active state. The crystal structure of GSK3β peptide with an activated Akt ternary complex has been reported [151-154]. This may enable the design of small molecules that will disrupt the interaction of upstream kinases and GSK3β [Therapeutic strategy-I, Fig. Fig.4]4] and thus prevent inhibitory kinases from associating with GSK3β. After checking the status of those patients who have inactivated GSK3β, Adenoviral vector carrying Ala9GSK3β may be tested along with other (chemo/radio) therapy, or with Ad-p53 (WT), which is known to block the progression of oral cancer to a certain extent [155]. However, although the chances are remote, some OSCC tumors will contain active GSK3β. It will be easy to test the inhibitors of GSK3 in these cases. The use of LiCl and SB-216763 in ovarian cancer [156]; LiCl and TDZD-8 in prostate cancer [157]; TDZD-8, SB-216763 and AR-A014418 in colorectal cancer [158,159]; LiCl, SB-216763, and TDZD-8 in myeloma [83]; TDZD-8 in AML and AML progenitor and stem cell cancer [160]; and LiCl and AR-A014418 in pancreatic cancer [161-163] has been evaluated, with positive outcomes. Almost all GSK3 inhibitors are able to inhibit two isoforms of GSK3 (α & β) with similar potency. The production and clinical evaluation of small-molecule inhibitors of particular isoforms will improve the chances of successful treatment in the future. Recent advancements in molecular biology have proven the effectiveness of small RNA interference (RNAi) in reducing the level of one protein by promoting mRNA degradation. This has been tried in an animal model of OSCC and as an alternative therapeutic strategy in patients who have developed drug resistance [164,165]. Similarly, RNAi has been used to counteract the overexpression of GSK3β in pancreatic [163], gastrointestinal [166], and prostate cancer [157], and it may be tried for OSCC.

Conclusion

The goal of cancer drug discovery is to design non-toxic therapeutics that will be free of side effects. Thanks to a deepening understanding of cell biology and technological advancements, the concept of cancer therapy is being fine-tuned every day. Beginning with metabolic enzyme targeting using folate and methotrexate, to targeting of DNA polymerase and topoisomerase (tamoxifen), to selective hormonal targeting of estrogens/androgens via their nuclear hormone receptors, to the more recent advancement of targeting human growth factor receptor kinases and their effectors, the gradual improvements in our understanding of cancer biology have led to new and numerous therapeutics. Recent developments in molecular research have led to the hypothesis of "oncogene addiction," which suggest the continuous dependence of tumor cells on these oncogenes [167]. The inactivation of GSK3β in OSCC may behave like an oncogene, and its gradual/sustained inactivation may promote oral cancer. Though most of the upstream and downstream targets and their expression status correlate with the understanding of GSK3β inactivation, real, direct assessment should be attempted. If the activated form of GSK3β is non-toxic to normal oral epithelial cells, as was found in animal models [150], then the manipulation of the activated GSK3β provides hope for treating oral cancer. Unlike other molecules, GSK3β is one of the most attractive targets and is well understood because of extensive prior research on it. Therefore, it should be evaluated thoroughly as a potential target for the treatment of oral cancer.

Competing interests

The authors declare that they have no competing interest.

Authors' contributions

RM reviewed the literature, drafted and finalized the manuscript.

Acknowledgements

The author apologizes to those workers whose works have not been included. RM acknowledges his mentor, Prof. A. Rana, Prof. B.R. Das, and Prof. D.P. Sarkar for what he learns from them in his scientific career and personal life.

References

  • Cheong SC, Chandramouli GV, Saleh A, Zain RB, Lau SH, Sivakumaren S, Pathmanathan R, Prime SS, Teo SH, Patel V, Gutkind JS. Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure. Oral Oncol. 2009;45:712–719. doi: 10.1016/j.oraloncology.2008.11.002. [PubMed] [Cross Ref]
  • Mishra A, Bharti AC, Saluja D, Das BC. Transactivation and expression patterns of Jun and Fos/AP-1 super-family proteins in human oral cancer. Int J Cancer. 2010;126:819–829. [PubMed]
  • Scully C, Bagan JV. Recent advances in oral oncology 2008; squamous cell carcinoma imaging, treatment, prognostication and treatment outcomes. Oral Oncol. 2009;45:e25–30. doi: 10.1016/j.oraloncology.2008.12.011. [PubMed] [Cross Ref]
  • zur Hausen H. Papillomaviruses in the causation of human cancers - a brief historical account. Virology. 2009;384:260–265. doi: 10.1016/j.virol.2008.11.046. [PubMed] [Cross Ref]
  • Paterson IC, Eveson JW, Prime SS. Molecular changes in oral cancer may reflect aetiology and ethnic origin. Eur J Cancer B Oral Oncol. 1996;32B:150–153. doi: 10.1016/0964-1955(95)00065-8. [PubMed] [Cross Ref]
  • Hamakawa H, Nakashiro K, Sumida T, Shintani S, Myers JN, Takes RP, Rinaldo A, Ferlito A. Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer. Head Neck. 2008;30:800–809. doi: 10.1002/hed.20830. [PubMed] [Cross Ref]
  • Kim M, Datta A, Brakeman P, Yu W, Mostov KE. Polarity proteins PAR6 and aPKC regulate cell death through GSK-3beta in 3D epithelial morphogenesis. J Cell Sci. 2007;120:2309–2317. doi: 10.1242/jcs.007443. [PubMed] [Cross Ref]
  • Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003;116:1175–1186. doi: 10.1242/jcs.00384. [PMC free article] [PubMed] [Cross Ref]
  • Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR, Mills GB. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA. 2000;97:11960–11965. doi: 10.1073/pnas.220413597. [PubMed] [Cross Ref]
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–789. doi: 10.1038/378785a0. [PubMed] [Cross Ref]
  • Kim MJ, Lee JH, Kim YK, Myoung H, Yun PY. The role of tamoxifen in combination with cisplatin on oral squamous cell carcinoma cell lines. Cancer Lett. 2007;245:284–292. doi: 10.1016/j.canlet.2006.01.017. [PubMed] [Cross Ref]
  • Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994;303(Pt 3):701–704. [PubMed]
  • Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993;296(Pt 1):15–19. [PubMed]
  • Lim J, Kim JH, Paeng JY, Kim MJ, Hong SD, Lee JI, Hong SP. Prognostic value of activated Akt expression in oral squamous cell carcinoma. J Clin Pathol. 2005;58:1199–1205. doi: 10.1136/jcp.2004.024786. [PMC free article] [PubMed] [Cross Ref]
  • Wu HT, Ko SY, Fong JH, Chang KW, Liu TY, Kao SY. Expression of phosphorylated Akt in oral carcinogenesis and its induction by nicotine and alkaline stimulation. J Oral Pathol Med. 2009;38:206–213. [PubMed]
  • Iamaroon A, Krisanaprakornkit S. Overexpression and activation of Akt2 protein in oral squamous cell carcinoma. Oral Oncol. 2009;45:e175–179. doi: 10.1016/j.oraloncology.2009.06.003. [PubMed] [Cross Ref]
  • Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980;107:519–527. [PubMed]
  • Woodgett JR. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 1990;9:2431–2438. [PubMed]
  • Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J. 2001;359:1–16. doi: 10.1042/0264-6021:3590001. [PubMed] [Cross Ref]
  • Luo J. Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett. 2009;273:194–200. doi: 10.1016/j.canlet.2008.05.045. [PubMed] [Cross Ref]
  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–1934. doi: 10.1126/science.1075762. [PubMed] [Cross Ref]
  • Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002;2:740–749. doi: 10.1038/nrc906. [PubMed] [Cross Ref]
  • Tsai WC, Tsai ST, Ko JY, Jin YT, Li C, Huang W, Young KC, Lai MD, Liu HS, Wu LW. The mRNA profile of genes in betel quid chewing oral cancer patients. Oral Oncol. 2004;40:418–426. doi: 10.1016/j.oraloncology.2003.09.015. [PubMed] [Cross Ref]
  • de Groot RP, Auwerx J, Bourouis M, Sassone-Corsi P. Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. Oncogene. 1993;8:841–847. [PubMed]
  • Buss H, Dorrie A, Schmitz ML, Frank R, Livingstone M, Resch K, Kracht M. Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. J Biol Chem. 2004;279:49571–49574. doi: 10.1074/jbc.C400442200. [PubMed] [Cross Ref]
  • Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004;23:2116–2125. doi: 10.1038/sj.emboj.7600217. [PubMed] [Cross Ref]
  • Ciani L, Salinas PC. WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci. 2005;6:351–362. doi: 10.1038/nrn1665. [PubMed] [Cross Ref]
  • Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398–1406. doi: 10.1038/ncb1508. [PubMed] [Cross Ref]
  • GA M, Uddin S, Mahmud D, Damacela I, Lavelle D, Ahmed M, van Besien K, Wickrema A. Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway. Biochem Biophys Res Commun. 2002;297:760–764. doi: 10.1016/S0006-291X(02)02278-7. [PubMed] [Cross Ref]
  • Ross SE, Erickson RL, Hemati N, MacDougald OA. Glycogen synthase kinase 3 is an insulin-regulated C/EBPalpha kinase. Mol Cell Biol. 1999;19:8433–8441. [PMC free article] [PubMed]
  • Gotschel F, Kern C, Lang S, Sparna T, Markmann C, Schwager J, McNelly S, von Weizsacker F, Laufer S, Hecht A, Merfort I. Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis. Exp Cell Res. 2008;314:1351–1366. doi: 10.1016/j.yexcr.2007.12.015. [PubMed] [Cross Ref]
  • de Sousa SO, Mesquita RA, Pinto DS Jr, Gutkind S. Immunolocalization of c-Fos and c-Jun in human oral mucosa and in oral squamous cell carcinoma. J Oral Pathol Med. 2002;31:78–81. [PubMed]
  • Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991;353:670–674. doi: 10.1038/353670a0. [PubMed] [Cross Ref]
  • Chen RH, Juo PC, Curran T, Blenis J. Phosphorylation of c-Fos at the C-terminus enhances its transforming activity. Oncogene. 1996;12:1493–1502. [PubMed]
  • Mishra A, Bharti AC, Varghese P, Saluja D, Das BC. Differential expression and activation of NF-kappaB family proteins during oral carcinogenesis: Role of high risk human papillomavirus infection. Int J Cancer. 2006;119:2840–2850. doi: 10.1002/ijc.22262. [PubMed] [Cross Ref]
  • Sasahira T, Kirita T, Oue N, Bhawal UK, Yamamoto K, Fujii K, Ohmori H, Luo Y, Yasui W, Bosserhoff AK, Kuniyasu H. High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma. Cancer Sci. 2008;99:1806–1812. [PubMed]
  • Ma Y, Wang M, Li N, Wu R, Wang X. Bleomycin-induced nuclear factor-kappaB activation in human bronchial epithelial cells involves the phosphorylation of glycogen synthase kinase 3beta. Toxicol Lett. 2009;187:194–200. doi: 10.1016/j.toxlet.2009.02.023. [PubMed] [Cross Ref]
  • Sanchez JF, Sniderhan LF, Williamson AL, Fan S, Chakraborty-Sett S, Maggirwar SB. Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling. Mol Cell Biol. 2003;23:4649–4662. doi: 10.1128/MCB.23.13.4649-4662.2003. [PMC free article] [PubMed] [Cross Ref]
  • Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol. 2005;168:29–33. doi: 10.1083/jcb.200409067. [PMC free article] [PubMed] [Cross Ref]
  • Tian D, Zhu M, Chen WS, Li JS, Wu RL, Wang X. Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cells. Food Chem Toxicol. 2006;44:1590–1596. doi: 10.1016/j.fct.2006.03.013. [PubMed] [Cross Ref]
  • Vora HH, Shah NG, Trivedi TI, Goswami JV, Shukla SN, Shah PM. Expression of C-Myc mRNA in squamous cell carcinoma of the tongue. J Surg Oncol. 2007;95:70–78. doi: 10.1002/jso.20675. [PubMed] [Cross Ref]
  • Baral R, Patnaik S, Das BR. Co-overexpression of p53 and c-myc proteins linked with advanced stages of betel- and tobacco-related oral squamous cell carcinomas from eastern India. Eur J Oral Sci. 1998;106:907–913. doi: 10.1046/j.0909-8836.1998.eos106502.x. [PubMed] [Cross Ref]
  • Mahomed F, Altini M, Meer S. Altered E-cadherin/beta-catenin expression in oral squamous carcinoma with and without nodal metastasis. Oral Dis. 2007;13:386–392. doi: 10.1111/j.1601-0825.2006.01295.x. [PubMed] [Cross Ref]
  • Tanaka N, Odajima T, Ogi K, Ikeda T, Satoh M. Expression of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br J Cancer. 2003;89:557–563. doi: 10.1038/sj.bjc.6601124. [PMC free article] [PubMed] [Cross Ref]
  • Bankfalvi A, Krassort M, Vegh A, Felszeghy E, Piffko J. Deranged expression of the E-cadherin/beta-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomas. J Oral Pathol Med. 2002;31:450–457. doi: 10.1034/j.1600-0714.2002.00147.x. [PubMed] [Cross Ref]
  • de Castro J, Gamallo C, Palacios J, Moreno-Bueno G, Rodriguez N, Feliu J, Gonzalez-Baron M. beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. Virchows Arch. 2000;437:599–604. doi: 10.1007/s004280000266. [PubMed] [Cross Ref]
  • Bahram F, von der Lehr N, Cetinkaya C, Larsson LG. c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood. 2000;95:2104–2110. [PubMed]
  • Oster SK, Ho CS, Soucie EL, Penn LZ. The myc oncogene: MarvelouslY Complex. Adv Cancer Res. 2002;84:81–154. full_text. [PubMed]
  • Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem. 2003;278:51606–51612. doi: 10.1074/jbc.M310722200. [PubMed] [Cross Ref]
  • An J, Yang DY, Xu QZ, Zhang SM, Huo YY, Shang ZF, Wang Y, Wu DC, Zhou PK. DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein. Mol Cancer. 2008;7:32. doi: 10.1186/1476-4598-7-32. [PMC free article] [PubMed] [Cross Ref]
  • Sogabe Y, Suzuki H, Toyota M, Ogi K, Imai T, Nojima M, Sasaki Y, Hiratsuka H, Tokino T. Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma. Int J Oncol. 2008;32:1253–1261. [PubMed]
  • Iwai S, Katagiri W, Kong C, Amekawa S, Nakazawa M, Yura Y. Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131:773–782. doi: 10.1007/s00432-005-0027-y. [PubMed] [Cross Ref]
  • Yeh KT, Chang JG, Lin TH, Wang YF, Chang JY, Shih MC, Lin CC. Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer. Int J Oncol. 2003;23:1001–1007. [PubMed]
  • Franz M, Spiegel K, Umbreit C, Richter P, Codina-Canet C, Berndt A, Altendorf-Hofmann A, Koscielny S, Hyckel P, Kosmehl H, Virtanen I. Expression of Snail is associated with myofibroblast phenotype development in oral squamous cell carcinoma. Histochem Cell Biol. 2009;131:651–660. doi: 10.1007/s00418-009-0559-3. [PubMed] [Cross Ref]
  • Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931–940. doi: 10.1038/ncb1173. [PubMed] [Cross Ref]
  • Doble BW, Woodgett JR. Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells Tissues Organs. 2007;185:73–84. doi: 10.1159/000101306. [PubMed] [Cross Ref]
  • Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431–442. doi: 10.1038/sj.cdd.4401183. [PubMed] [Cross Ref]
  • Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS. Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem. 2003;278:48872–48879. doi: 10.1074/jbc.M305870200. [PMC free article] [PubMed] [Cross Ref]
  • Eom TY, Jope RS. GSK3 beta N-terminus binding to p53 promotes its acetylation. Mol Cancer. 2009;8:14. doi: 10.1186/1476-4598-8-14. [PMC free article] [PubMed] [Cross Ref]
  • Ma C, Wang J, Gao Y, Gao TW, Chen G, Bower KA, Odetallah M, Ding M, Ke Z, Luo J. The role of glycogen synthase kinase 3beta in the transformation of epidermal cells. Cancer Res. 2007;67:7756–7764. doi: 10.1158/0008-5472.CAN-06-4665. [PubMed] [Cross Ref]
  • Chun KH, Lee HY, Hassan K, Khuri F, Hong WK, Lotan R. Implication of protein kinase B/Akt and Bcl-2/Bcl-XL suppression by the farnesyl transferase inhibitor SCH66336 in apoptosis induction in squamous carcinoma cells. Cancer Res. 2003;63:4796–4800. [PubMed]
  • Amornphimoltham P, Sriuranpong V, Patel V, Benavides F, Conti CJ, Sauk J, Sausville EA, Molinolo AA, Gutkind JS. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res. 2004;10:4029–4037. doi: 10.1158/1078-0432.CCR-03-0249. [PubMed] [Cross Ref]
  • Suzuki M, Shinohara F, Endo M, Sugazaki M, Echigo S, Rikiishi H. Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells. Cancer Chemother Pharmacol. 2009;64:223–232. doi: 10.1007/s00280-008-0833-4. [PubMed] [Cross Ref]
  • Bauer K, Dowejko A, Bosserhoff AK, Reichert TE, Bauer RJ. P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation. Carcinogenesis. 2009;30:1781–1788. doi: 10.1093/carcin/bgp175. [PubMed] [Cross Ref]
  • Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–166. doi: 10.1038/nrc2602. [PubMed] [Cross Ref]
  • Sartor M, Steingrimsdottir H, Elamin F, Gaken J, Warnakulasuriya S, Partridge M, Thakker N, Johnson NW, Tavassoli M. Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines. Br J Cancer. 1999;80:79–86. doi: 10.1038/sj.bjc.6690505. [PMC free article] [PubMed] [Cross Ref]
  • Turatti E, da Costa Neves A, de Magalhaes MH, de Sousa SO. Assessment of c-Jun, c-Fos and cyclin D1 in premalignant and malignant oral lesions. J Oral Sci. 2005;47:71–76. doi: 10.2334/josnusd.47.71. [PubMed] [Cross Ref]
  • Mihara M, Shintani S, Nakahara Y, Kiyota A, Ueyama Y, Matsumura T, Wong DT. Overexpression of CDK2 is a prognostic indicator of oral cancer progression. Jpn J Cancer Res. 2001;92:352–360. [PubMed]
  • Fraczek M, Wozniak Z, Ramsey D, Krecicki T. Expression patterns of cyclin E, cyclin A and CDC25 phosphatases in laryngeal carcinogenesis. Eur Arch Otorhinolaryngol. 2007;264:923–928. doi: 10.1007/s00405-007-0276-2. [PubMed] [Cross Ref]
  • Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499–3511. doi: 10.1101/gad.12.22.3499. [PubMed] [Cross Ref]
  • Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M, Clurman BE, Roberts JM. Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell. 2003;12:381–392. doi: 10.1016/S1097-2765(03)00287-9. [PubMed] [Cross Ref]
  • Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM. Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis. Mol Carcinog. 2002;35:180–185. doi: 10.1002/mc.10087. [PubMed] [Cross Ref]
  • Goto H, Kawano K, Kobayashi I, Sakai H, Yanagisawa S. Expression of cyclin D1 and GSK-3beta and their predictive value of prognosis in squamous cell carcinomas of the tongue. Oral Oncol. 2002;38:549–556. doi: 10.1016/S1368-8375(01)00121-X. [PubMed] [Cross Ref]
  • Tokumaru Y, Yamashita K, Osada M, Nomoto S, Sun DI, Xiao Y, Hoque MO, Westra WH, Califano JA, Sidransky D. Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing. Cancer Res. 2004;64:5982–5987. doi: 10.1158/0008-5472.CAN-04-0993. [PubMed] [Cross Ref]
  • Yamazaki K, Hasegawa M, Ohoka I, Hanami K, Asoh A, Nagao T, Sugano I, Ishida Y. Increased E2F-1 expression via tumour cell proliferation and decreased apoptosis are correlated with adverse prognosis in patients with squamous cell carcinoma of the oesophagus. J Clin Pathol. 2005;58:904–910. doi: 10.1136/jcp.2004.023127. [PMC free article] [PubMed] [Cross Ref]
  • Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008;8:976–990. doi: 10.1038/nrc2231. [PubMed] [Cross Ref]
  • Miliani de Marval PL, Macias E, Rounbehler R, Sicinski P, Kiyokawa H, Johnson DG, Conti CJ, Rodriguez-Puebla ML. Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol. 2004;24:7538–7547. doi: 10.1128/MCB.24.17.7538-7547.2004. [PMC free article] [PubMed] [Cross Ref]
  • Nadal A, Jares P, Pinyol M, Conde L, Romeu C, Fernandez PL, Campo E, Cardesa A. Association of CDK4 and CCND1 mRNA overexpression in laryngeal squamous cell carcinomas occurs without CDK4 amplification. Virchows Arch. 2007;450:161–167. doi: 10.1007/s00428-006-0314-2. [PubMed] [Cross Ref]
  • Nemes JA, Nemes Z, Marton IJ. p21WAF1/CIP1 expression is a marker of poor prognosis in oral squamous cell carcinoma. J Oral Pathol Med. 2005;34:274–279. doi: 10.1111/j.1600-0714.2005.00310.x. [PubMed] [Cross Ref]
  • Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M. Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol. 2003;22:891–898. [PubMed]
  • Rossig L, Badorff C, Holzmann Y, Zeiher AM, Dimmeler S. Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation. J Biol Chem. 2002;277:9684–9689. doi: 10.1074/jbc.M106157200. [PubMed] [Cross Ref]
  • Kudo Y, Kitajima S, Ogawa I, Miyauchi M, Takata T. Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma. Oral Oncol. 2005;41:105–116. doi: 10.1016/j.oraloncology.2004.05.003. [PubMed] [Cross Ref]
  • Zhou Y, Uddin S, Zimmerman T, Kang JA, Ulaszek J, Wickrema A. Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3. Leuk Lymphoma. 2008;49:1945–1953. doi: 10.1080/10428190802304966. [PMC free article] [PubMed] [Cross Ref]
  • Reagan-Shaw S, Ahmad N. RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cells. Cancer Res. 2006;66:1062–1069. doi: 10.1158/0008-5472.CAN-05-1018. [PubMed] [Cross Ref]
  • Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q. The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res. 2005;11:6442–6449. doi: 10.1158/1078-0432.CCR-05-0267. [PubMed] [Cross Ref]
  • Chen JC, Lu KW, Tsai ML, Hsu SC, Kuo CL, Yang JS, Hsia TC, Yu CS, Chou ST, Kao MC. Gypenosides induced G0/G1 arrest via CHk2 and apoptosis through endoplasmic reticulum stress and mitochondria-dependent pathways in human tongue cancer SCC-4 cells. Oral Oncol. 2009;45:273–283. doi: 10.1016/j.oraloncology.2008.05.012. [PubMed] [Cross Ref]
  • Obaya AJ, Mateyak MK, Sedivy JM. Mysterious liaisons: the relationship between c-Myc and the cell cycle. Oncogene. 1999;18:2934–2941. doi: 10.1038/sj.onc.1202749. [PubMed] [Cross Ref]
  • Kang T, Wei Y, Honaker Y, Yamaguchi H, Appella E, Hung MC, Piwnica-Worms H. GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell. 2008;13:36–47. doi: 10.1016/j.ccr.2007.12.002. [PMC free article] [PubMed] [Cross Ref]
  • Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161:1881–1891. [PubMed]
  • Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM, Teng SC, Wu KJ. Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene. 2007;26:1459–1467. doi: 10.1038/sj.onc.1209929. [PubMed] [Cross Ref]
  • Kosmehl H, Berndt A, Strassburger S, Borsi L, Rousselle P, Mandel U, Hyckel P, Zardi L, Katenkamp D. Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma. Br J Cancer. 1999;81:1071–1079. doi: 10.1038/sj.bjc.6690809. [PMC free article] [PubMed] [Cross Ref]
  • Mhawech P, Dulguerov P, Assaly M, Ares C, Allal AS. EB-D fibronectin expression in squamous cell carcinoma of the head and neck. Oral Oncol. 2005;41:82–88. doi: 10.1016/j.oraloncology.2004.07.003. [PubMed] [Cross Ref]
  • de Nigris F, Botti C, Rossiello R, Crimi E, Sica V, Napoli C. Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha3beta1-integrin in tumour cells. Oncogene. 2007;26:382–394. doi: 10.1038/sj.onc.1209804. [PubMed] [Cross Ref]
  • Haraguchi M, Okubo T, Miyashita Y, Miyamoto Y, Hayashi M, Crotti TN, McHugh KP, Ozawa M. Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins. J Biol Chem. 2008;283:23514–23523. doi: 10.1074/jbc.M801125200. [PubMed] [Cross Ref]
  • Erdem NF, Carlson ER, Gerard DA, Ichiki AT. Characterization of 3 oral squamous cell carcinoma cell lines with different invasion and/or metastatic potentials. J Oral Maxillofac Surg. 2007;65:1725–1733. doi: 10.1016/j.joms.2006.11.034. [PubMed] [Cross Ref]
  • Ziober BL, Silverman SS Jr, Kramer RH. Adhesive mechanisms regulating invasion and metastasis in oral cancer. Crit Rev Oral Biol Med. 2001;12:499–510. doi: 10.1177/10454411010120060401. [PubMed] [Cross Ref]
  • Kornberg LJ. Focal adhesion kinase expression in oral cancers. Head Neck. 1998;20:634–639. doi: 10.1002/(SICI)1097-0347(199810)20:7<634::AID-HED10>3.0.CO;2-M. [PubMed] [Cross Ref]
  • Ko BS, Chang TC, Chen CH, Liu CC, Kuo CC, Hsu C, Shen YC, Shen TL, Golubovskaya VM, Chang CC. Bortezomib suppresses focal adhesion kinase expression via interrupting nuclear factor-kappa B. Life Sci. 2010;86:199–206. doi: 10.1016/j.lfs.2009.12.003. [PubMed] [Cross Ref]
  • Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E. Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J. 2005;391:359–370. doi: 10.1042/BJ20050282. [PubMed] [Cross Ref]
  • Ramos DM, Dang D, Sadler S. The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer. Anticancer Res. 2009;29:125–130. [PubMed]
  • Han S, Roman J. COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. Int J Cancer. 2005;116:536–546. doi: 10.1002/ijc.21125. [PubMed] [Cross Ref]
  • Zutter MM, Santoro SA, Painter AS, Tsung YL, Gafford A. The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expression. J Biol Chem. 1994;269:463–469. [PubMed]
  • Nishida K, Kitazawa R, Mizuno K, Maeda S, Kitazawa S. Identification of regulatory elements of human alpha 6 integrin subunit gene. Biochem Biophys Res Commun. 1997;241:258–263. doi: 10.1006/bbrc.1997.7808. [PubMed] [Cross Ref]
  • Corbi AL, Jensen UB, Watt FM. The alpha2 and alpha5 integrin genes: identification of transcription factors that regulate promoter activity in epidermal keratinocytes. FEBS Lett. 2000;474:201–207. doi: 10.1016/S0014-5793(00)01591-X. [PubMed] [Cross Ref]
  • Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132:3151–3161. doi: 10.1242/dev.01907. [PubMed] [Cross Ref]
  • Jordan RC, Macabeo-Ong M, Shiboski CH, Dekker N, Ginzinger DG, Wong DT, Schmidt BL. Overexpression of matrix metalloproteinase-1 and -9 mRNA is associated with progression of oral dysplasia to cancer. Clin Cancer Res. 2004;10:6460–6465. doi: 10.1158/1078-0432.CCR-04-0656. [PubMed] [Cross Ref]
  • Katayama A, Bandoh N, Kishibe K, Takahara M, Ogino T, Nonaka S, Harabuchi Y. Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis. Clin Cancer Res. 2004;10:634–640. doi: 10.1158/1078-0432.CCR-0864-02. [PubMed] [Cross Ref]
  • Sutinen M, Kainulainen T, Hurskainen T, Vesterlund E, Alexander JP, Overall CM, Sorsa T, Salo T. Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis. Br J Cancer. 1998;77:2239–2245. [PMC free article] [PubMed]
  • Impola U, Uitto VJ, Hietanen J, Hakkinen L, Zhang L, Larjava H, Isaka K, Saarialho-Kere U. Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancer. J Pathol. 2004;202:14–22. doi: 10.1002/path.1479. [PubMed] [Cross Ref]
  • Kinugasa Y, Hatori M, Ito H, Kurihara Y, Ito D, Nagumo M. Inhibition of cyclooxygenase-2 suppresses invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 and CD44. Clin Exp Metastasis. 2004;21:737–745. doi: 10.1007/s10585-005-1190-x. [PubMed] [Cross Ref]
  • Kosunen A, Pirinen R, Ropponen K, Pukkila M, Kellokoski J, Virtaniemi J, Sironen R, Juhola M, Kumpulainen E, Johansson R. CD44 expression and its relationship with MMP-9, clinicopathological factors and survival in oral squamous cell carcinoma. Oral Oncol. 2007;43:51–59. doi: 10.1016/j.oraloncology.2006.01.003. [PubMed] [Cross Ref]
  • Lee CH, Liu SY, Lin MH, Chiang WF, Chen TC, Huang WT, Chou DS, Chiu CT, Liu YC. Upregulation of matrix metalloproteinase-1 (MMP-1) expression in oral carcinomas of betel quid (BQ) users: roles of BQ ingredients in the acceleration of tumour cell motility through MMP-1. Arch Oral Biol. 2008;53:810–818. doi: 10.1016/j.archoralbio.2008.05.004. [PubMed] [Cross Ref]
  • Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, Nagayama M. Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol. 2001;37:65–71. doi: 10.1016/S1368-8375(00)00059-2. [PubMed] [Cross Ref]
  • Taki M, Kamata N, Yokoyama K, Fujimoto R, Tsutsumi S, Nagayama M. Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci. 2003;94:593–597. doi: 10.1111/j.1349-7006.2003.tb01488.x. [PubMed] [Cross Ref]
  • Schipper JH, Frixen UH, Behrens J, Unger A, Jahnke K, Birchmeier W. E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis. Cancer Res. 1991;51:6328–6337. [PubMed]
  • Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–89. doi: 10.1038/35000034. [PubMed] [Cross Ref]
  • Sappayatosok K, Maneerat Y, Swasdison S, Viriyavejakul P, Dhanuthai K, Zwang J, Chaisri U. Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in oral squamous cell carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlation. Med Oral Patol Oral Cir Bucal. 2009;14:E319–324. [PubMed]
  • Nystrom ML, McCulloch D, Weinreb PH, Violette SM, Speight PM, Marshall JF, Hart IR, Thomas GJ. Cyclooxygenase-2 inhibition suppresses alphavbeta6 integrin-dependent oral squamous carcinoma invasion. Cancer Res. 2006;66:10833–10842. doi: 10.1158/0008-5472.CAN-06-1640. [PubMed] [Cross Ref]
  • Kurihara Y, Hatori M, Ando Y, Ito D, Toyoshima T, Tanaka M, Shintani S. Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activation. Clin Exp Metastasis. 2009;26:425–432. doi: 10.1007/s10585-009-9241-3. [PubMed] [Cross Ref]
  • Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A, Dannenberg AJ. Inhibition of cyclooxygenase-2 gene expression by p53. J Biol Chem. 1999;274:10911–10915. doi: 10.1074/jbc.274.16.10911. [PubMed] [Cross Ref]
  • Chiang SL, Chen PH, Lee CH, Ko AM, Lee KW, Lin YC, Ho PS, Tu HP, Wu DC, Shieh TY, Ko YC. Up-regulation of inflammatory signalings by areca nut extract and role of cyclooxygenase-2 -1195G > a polymorphism reveal risk of oral cancer. Cancer Res. 2008;68:8489–8498. doi: 10.1158/0008-5472.CAN-08-0823. [PubMed] [Cross Ref]
  • Tamatani T, Azuma M, Ashida Y, Motegi K, Takashima R, Harada K, Kawaguchi S, Sato M. Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8. Int J Cancer. 2004;108:912–921. doi: 10.1002/ijc.11640. [PubMed] [Cross Ref]
  • Beurel E, Jope RS. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol. 2006;79:173–189. doi: 10.1016/j.pneurobio.2006.07.006. [PMC free article] [PubMed] [Cross Ref]
  • Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406:86–90. doi: 10.1038/35017574. [PubMed] [Cross Ref]
  • Tan J, Zhuang L, Leong HS, Iyer NG, Liu ET, Yu Q. Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. Cancer Res. 2005;65:9012–9020. doi: 10.1158/0008-5472.CAN-05-1226. [PubMed] [Cross Ref]
  • Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002;35:605–623. doi: 10.1016/S0896-6273(02)00828-0. [PubMed] [Cross Ref]
  • Uchida M, Iwase M, Takaoka S, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M, Shintani S. Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors. Int J Oncol. 2007;30:1163–1171. [PubMed]
  • Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W. t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. Cancer Res. 2008;68:395–403. doi: 10.1158/0008-5472.CAN-07-1580. [PubMed] [Cross Ref]
  • Ballou LM, Tian PY, Lin HY, Jiang YP, Lin RZ. Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptor. J Biol Chem. 2001;276:40910–40916. doi: 10.1074/jbc.M103480200. [PubMed] [Cross Ref]
  • Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A. A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta) and mediates protein kinase A-dependent inhibition of GSK-3beta. J Biol Chem. 2002;277:36955–36961. doi: 10.1074/jbc.M206210200. [PubMed] [Cross Ref]
  • Arun P, Brown MS, Ehsanian R, Chen Z, Van Waes C. Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. Clin Cancer Res. 2009;15:5974–5984. doi: 10.1158/1078-0432.CCR-09-1352. [PMC free article] [PubMed] [Cross Ref]
  • Tosi L, Rinaldi E, Carinci F, Farina A, Pastore A, Pelucchi S, Cassano L, Evangelisti R, Carinci P, Volinia S. Akt, protein kinase C, and mitogen-activated protein kinase phosphorylation status in head and neck squamous cell carcinoma. Head Neck. 2005;27:130–137. doi: 10.1002/hed.20120. [PubMed] [Cross Ref]
  • Moral M, Paramio JM. Akt pathway as a target for therapeutic intervention in HNSCC. Histol Histopathol. 2008;23:1269–1278. [PubMed]
  • Tsai CH, Hsieh YS, Yang SF, Chou MY, Chang YC. Matrix metalloproteinase 2 and matrix metalloproteinase 9 expression in human oral squamous cell carcinoma and the effect of protein kinase C inhibitors: preliminary observations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:710–716. doi: 10.1067/moe.2003.121. [PubMed] [Cross Ref]
  • Pan Q, Bao LW, Teknos TN, Merajver SD. Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. Cancer Res. 2006;66:9379–9384. doi: 10.1158/0008-5472.CAN-06-2646. [PubMed] [Cross Ref]
  • Doehn U, Hauge C, Frank SR, Jensen CJ, Duda K, Nielsen JV, Cohen MS, Johansen JV, Winther BR, Lund LR. RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. Mol Cell. 2009;35:511–522. doi: 10.1016/j.molcel.2009.08.002. [PubMed] [Cross Ref]
  • Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, Jinawath N, Tsai MH, Chang NW, Lin CF. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69:2568–2576. doi: 10.1158/0008-5472.CAN-08-3199. [PubMed] [Cross Ref]
  • Saito Y, Vandenheede JR, Cohen P. The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells. Biochem J. 1994;303(Pt 1):27–31. [PubMed]
  • Amornphimoltham P, Patel V, Sodhi A, Nikitakis NG, Sauk JJ, Sausville EA, Molinolo AA, Gutkind JS. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res. 2005;65:9953–9961. doi: 10.1158/0008-5472.CAN-05-0921. [PubMed] [Cross Ref]
  • West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J Clin Invest. 2003;111:81–90. [PMC free article] [PubMed]
  • Hope BT, Nagarkar D, Leonard S, Wise RA. Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokers. J Neurosci. 2007;27:1964–1972. doi: 10.1523/JNEUROSCI.3661-06.2007. [PMC free article] [PubMed] [Cross Ref]
  • Du B, Altorki NK, Kopelovich L, Subbaramaiah K, Dannenberg AJ. Tobacco smoke stimulates the transcription of amphiregulin in human oral epithelial cells: evidence of a cyclic AMP-responsive element binding protein-dependent mechanism. Cancer Res. 2005;65:5982–5988. doi: 10.1158/0008-5472.CAN-05-0628. [PubMed] [Cross Ref]
  • Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol. 2002;3:461–469. doi: 10.1016/S1470-2045(02)00815-X. [PubMed] [Cross Ref]
  • Nakayama H, Numakawa T, Ikeuchi T. Nicotine-induced phosphorylation of Akt through epidermal growth factor receptor and Src in PC12h cells. J Neurochem. 2002;83:1372–1379. doi: 10.1046/j.1471-4159.2002.01248.x. [PubMed] [Cross Ref]
  • Sugano N, Minegishi T, Kawamoto K, Ito K. Nicotine inhibits UV-induced activation of the apoptotic pathway. Toxicol Lett. 2001;125:61–65. doi: 10.1016/S0378-4274(01)00416-7. [PubMed] [Cross Ref]
  • Etique N, Flament S, Lecomte J, Grillier-Vuissoz I. Ethanol-induced ligand-independent activation of ERalpha mediated by cyclic AMP/PKA signaling pathway: an in vitro study on MCF-7 breast cancer cells. Int J Oncol. 2007;31:1509–1518. [PubMed]
  • Pim D, Massimi P, Dilworth SM, Banks L. Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A. Oncogene. 2005;24:7830–7838. doi: 10.1038/sj.onc.1208935. [PubMed] [Cross Ref]
  • Perez-Plasencia C, Vazquez-Ortiz G, Lopez-Romero R, Pina-Sanchez P, Moreno J, Salcedo M. Genome wide expression analysis in HPV16 Cervical Cancer: identification of altered metabolic pathways. Infect Agent Cancer. 2007;2:16. doi: 10.1186/1750-9378-2-16. [PMC free article] [PubMed] [Cross Ref]
  • Sun Y. p53 and its downstream proteins as molecular targets of cancer. Mol Carcinog. 2006;45:409–415. doi: 10.1002/mc.20231. [PubMed] [Cross Ref]
  • Matsuda T, Zhai P, Maejima Y, Hong C, Gao S, Tian B, Goto K, Takagi H, Tamamori-Adachi M, Kitajima S, Sadoshima J. Distinct roles of GSK-3alpha and GSK-3beta phosphorylation in the heart under pressure overload. Proc Natl Acad Sci USA. 2008;105:20900–20905. doi: 10.1073/pnas.0808315106. [PubMed] [Cross Ref]
  • Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford D. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol. 2002;9:940–944. doi: 10.1038/nsb870. [PubMed] [Cross Ref]
  • Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J. 2003;22:494–501. doi: 10.1093/emboj/cdg068. [PubMed] [Cross Ref]
  • Bax B, Carter PS, Lewis C, Guy AR, Bridges A, Tanner R, Pettman G, Mannix C, Culbert AA, Brown MJ. The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. Structure. 2001;9:1143–1152. doi: 10.1016/S0969-2126(01)00679-7. [PubMed] [Cross Ref]
  • Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH. Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001;105:721–732. doi: 10.1016/S0092-8674(01)00374-9. [PubMed] [Cross Ref]
  • Clayman GL, el-Naggar AK, Lippman SM, Henderson YC, Frederick M, Merritt JA, Zumstein LA, Timmons TM, Liu TJ, Ginsberg L. Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol. 1998;16:2221–2232. [PubMed]
  • Cao Q, Lu X, Feng YJ. Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells. Cell Res. 2006;16:671–677. doi: 10.1038/sj.cr.7310078. [PubMed] [Cross Ref]
  • Sun A, Shanmugam I, Song J, Terranova PF, Thrasher JB, Li B. Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancer. Prostate. 2007;67:976–988. doi: 10.1002/pros.20586. [PubMed] [Cross Ref]
  • Ghosh JC, Altieri DC. Activation of p53-dependent apoptosis by acute ablation of glycogen synthase kinase-3beta in colorectal cancer cells. Clin Cancer Res. 2005;11:4580–4588. doi: 10.1158/1078-0432.CCR-04-2624. [PubMed] [Cross Ref]
  • Shakoori A, Mai W, Miyashita K, Yasumoto K, Takahashi Y, Ooi A, Kawakami K, Minamoto T. Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodents. Cancer Sci. 2007;98:1388–1393. doi: 10.1111/j.1349-7006.2007.00545.x. [PubMed] [Cross Ref]
  • Jordan CT. The leukemic stem cell. Best Pract Res Clin Haematol. 2007;20:13–18. doi: 10.1016/j.beha.2006.10.005. [PMC free article] [PubMed] [Cross Ref]
  • Ougolkov AV, Fernandez-Zapico ME, Bilim VN, Smyrk TC, Chari ST, Billadeau DD. Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activity and tumor dedifferentiation. Clin Cancer Res. 2006;12:5074–5081. doi: 10.1158/1078-0432.CCR-06-0196. [PMC free article] [PubMed] [Cross Ref]
  • Garcea G, Manson MM, Neal CP, Pattenden CJ, Sutton CD, Dennison AR, Berry DP. Glycogen synthase kinase-3 beta; a new target in pancreatic cancer? Curr Cancer Drug Targets. 2007;7:209–215. doi: 10.2174/156800907780618266. [PubMed] [Cross Ref]
  • Mamaghani S, Patel S, Hedley DW. Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy. BMC Cancer. 2009;9:132. doi: 10.1186/1471-2407-9-132. [PMC free article] [PubMed] [Cross Ref]
  • Zhou H, Tang Y, Liang X, Yang X, Yang J, Zhu G, Zheng M, Zhang C. RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo. Int J Cancer. 2009;125:453–462. doi: 10.1002/ijc.24360. [PubMed] [Cross Ref]
  • Lage H. Therapeutic potential of RNA interference in drug-resistant cancers. Future Oncol. 2009;5:169–185. doi: 10.2217/14796694.5.2.169. [PubMed] [Cross Ref]
  • Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T. Deregulated GSK3{beta} sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res. 2009;15:6810–6819. doi: 10.1158/1078-0432.CCR-09-0973. [PubMed] [Cross Ref]
  • Weinstein IB. Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 2002;297:63–64. doi: 10.1126/science.1073096. [PubMed] [Cross Ref]
  • Ding Q, He X, Xia W, Hsu JM, Chen CT, Li LY, Lee DF, Yang JY, Xie X, Liu JC, Hung MC. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res. 2007;67:4564–4571. doi: 10.1158/0008-5472.CAN-06-1788. [PubMed] [Cross Ref]
  • Farago M, Dominguez I, Landesman-Bollag E, Xu X, Rosner A, Cardiff RD, Seldin DC. Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis. Cancer Res. 2005;65:5792–5801. doi: 10.1158/0008-5472.CAN-05-1021. [PubMed] [Cross Ref]
  • Dong J, Peng J, Zhang H, Mondesire WH, Jian W, Mills GB, Hung MC, Meric-Bernstam F. Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res. 2005;65:1961–1972. doi: 10.1158/0008-5472.CAN-04-2501. [PubMed] [Cross Ref]
  • Dal Col J, Dolcetti R. GSK-3beta inhibition: at the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma. Cell Cycle. 2008;7:2813–2816. [PubMed]
  • Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ, Xu A. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res. 2006;66:11462–11470. doi: 10.1158/0008-5472.CAN-06-1969. [PubMed] [Cross Ref]
  • Morrison JA, Gulley ML, Pathmanathan R, Raab-Traub N. Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma. Cancer Res. 2004;64:5251–5260. doi: 10.1158/0008-5472.CAN-04-0538. [PubMed] [Cross Ref]
  • Zheng H, Saito H, Masuda S, Yang X, Takano Y. Phosphorylated GSK3beta-ser9 and EGFR are good prognostic factors for lung carcinomas. Anticancer Res. 2007;27:3561–3569. [PubMed]
  • Mai W, Miyashita K, Shakoori A, Zhang B, Yu ZW, Takahashi Y, Motoo Y, Kawakami K, Minamoto T. Detection of active fraction of glycogen synthase kinase 3beta in cancer cells by nonradioisotopic in vitro kinase assay. Oncology. 2006;71:297–305. doi: 10.1159/000106429. [PubMed] [Cross Ref]
  • Ougolkov AV, Fernandez-Zapico ME, Savoy DN, Urrutia RA, Billadeau DD. Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 2005;65:2076–2081. doi: 10.1158/0008-5472.CAN-04-3642. [PubMed] [Cross Ref]
  • Ougolkov AV, Billadeau DD. Targeting GSK-3: a promising approach for cancer therapy? Future Oncol. 2006;2:91–100. doi: 10.2217/14796694.2.1.91. [PubMed] [Cross Ref]
  • Bilim V, Ougolkov A, Yuuki K, Naito S, Kawazoe H, Muto A, Oya M, Billadeau D, Motoyama T, Tomita Y. Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma. Br J Cancer. 2009;101:2005–2014. doi: 10.1038/sj.bjc.6605437. [PMC free article] [PubMed] [Cross Ref]
  • Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, Newton IG, Giles FJ, Durocher J, Creusot RS, Karimi M. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci USA. 2009;106:3925–3929. doi: 10.1073/pnas.0900189106. [PubMed] [Cross Ref]
  • Ougolkov AV, Bone ND, Fernandez-Zapico ME, Kay NE, Billadeau DD. Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood. 2007;110:735–742. doi: 10.1182/blood-2006-12-060947. [PubMed] [Cross Ref]
  • Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature. 2008;455:1205–1209. doi: 10.1038/nature07284. [PubMed] [Cross Ref]
  • Adler JT, Cook M, Luo Y, Pitt SC, Ju J, Li W, Shen B, Kunnimalaiyaan M, Chen H. Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3beta. Mol Cancer Ther. 2009;8:914–920. doi: 10.1158/1535-7163.MCT-08-0712. [PMC free article] [PubMed] [Cross Ref]
  • Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, Bailey R, Maric D, Zenklusen JC, Lee J, Fine HA. Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. Cancer Res. 2008;68:6643–6651. doi: 10.1158/0008-5472.CAN-08-0850. [PMC free article] [PubMed] [Cross Ref]

Articles from Molecular Cancer are provided here courtesy of BioMed Central