The Neuronally expressed developmentally downregulated 4 (NEDD4), functioning largely as an E3 ubiquitin ligase, has been demonstrated to play a critical role in the development and progression of human cancers. In this review, to understand the regulatory mechanism(s) of NEDD4 as well as the signaling pathways controlled by NEDD4, we briefly describe the NEDD4 upstream regulators and its downstream ubiquitin substrates. Moreover, we further discuss its oncogenic roles in human malignancies. Therefore, targeting NEDD4 could be a potential therapeutic strategy for treatment of human cancers.
Cancer; E3 ligase; NEDD4; oncogene; target; therapy; ubiquitination
Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZ-based therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers.
Bortezomib; carfilzomib; combination therapy; immunoproteasomes; multiple myeloma; proteasome inhibitor; resistance to proteasome inhibitors; ubiquitin-proteasome pathway
The cyclic-AMP response element-binding protein (CREB) is a nuclear transcription factor activated by phosphorylation at Ser133 by multiple serine/threonine (Ser/Thr) kinases. Upon phosphorylation, CREB binds the transcriptional co-activator, CBP (CREB-binding protein), to initiate CREB-dependent gene transcription. CREB is a critical regulator of cell differentiation, proliferation and survival in the nervous system. Recent studies have shown that CREB is involved tumor initiation, progression and metastasis, supporting its role as a proto-oncogene. Overexpression and over-activation of CREB were observed in cancer tissues from patients with prostate cancer, breast cancer, non-small-cell lung cancer and acute leukemia while down-regulation of CREB in several distinct cancer cell lines resulted in inhibition of cell proliferation and induction of apoptosis, suggesting that CREB may be a promising target for cancer therapy. Although CREB, as a transcription factor, is a challenging target for small molecules, various small molecules have been discovered to inhibit CREB phosphorylation, CREB-DNA, or CREB-CBP interaction. These results suggest that CREB is a suitable transcription factor for drug targeting and therefore targeting CREB could represent a novel strategy for cancer therapy.
Cancer; CBP; CREB; inhibitors; KID; KIX; naphthol AS-E; Ro 31-8220
There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.
Chalcones; molecular targets; bioactive dietary compounds; chemoprevention
Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-κB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-κB leads to radiosensitization in radioresistant cancer cells. NF-κB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-κB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-κB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-κB in response to IR. Also, the association of ATM with the NF-κB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.
ATM; NF-κB; ionizing radiation
Gastrointestinal (GI) cancer is characterized by its aggressiveness, but the underlying mechanism is not fully understood. Studies reveal that epithelial to mesenchymal transition (EMT), which is regulated by a series of transcription factors and signaling pathways, is strongly associated with GI cancer cell proliferation, invasion and metastasis. In essential, EMT is a product of crosstalk between signaling pathways. Krüppel-like factor 4 (KLF4), a zinc finger-type transcription factor, is decreased or lost in most GI cancers. By transcriptional regulating its downstream target genes, KLF4 plays important roles of GI cancer tumorigenesis, proliferation and differentiation. In this review, we focus on the mechanism of KLF4 in GI cancer EMT, and demonstrate that through crosstalk with TGF-β, Notch, and Wnt signaling pathways, KLF4 negatively regulates EMT of GI cancers. Finally, we indicate the challenging new frontiers for KLF4 which contributes to better understanding of the mechanism of GI cancer aggressiveness.
KLF4; gastrointestinal cancer; EMT; TGF-β; Notch; Wnt
Epithelial-mesenchymal transition (EMT) is a developmental process that converts epithelial cells into migratory and invasive cells. This process also plays an important role in cancer progression and metastasis by enabling tumor cells to leave primary sites. EMT is regulated by complex transcription networks and post-transcriptional modulators. MicroRNAs are single-stranded non-coding RNAs that represent a novel class of gene regulators. It has been shown that microRNAs are critical regulators of EMT process. The molecular mechanisms of EMT modulation by microRNAs include the suppression of transcription factors that directly regulate EMT and the down-regulation of cellular genes and pathways that are indirectly involved in EMT process. The expressions of microRNAs that control EMT process are dysregulated in cancer. In this review, we summarize the recent progress of microRNAs in EMT regulation.
microRNA; cancer; epithelial-mesenchymal transition; transcription; non-coding RNA; migration
Hepatocellular cancer (HCC) is the third cause of death by cancer worldwide. In the current study we target β-catenin, an oncogene mutated and constitutively active in 20–30% of HCCs, via a novel, cell permeable gamma guanidine-based peptide nucleic acid (γGPNA) antisense oligonucleotide designed against either the transcription or the translation start site of the human β-catenin gene. Using TOPflash, a luciferase reporter assay, we show that γGPNA targeting the transcription start site showed more robust activity against β-catenin activity in liver tumor cells that harbor β-catenin gene mutations (HepG2 & Snu-449). We identified concomitant suppression of β-catenin expression and of various Wnt targets including glutamine synthetase (GS) and cyclin-D1. Concurrently, γGPNA treatment reduced proliferation, survival and viability of HCC cells. Intriguingly, an angiogenesis quantitative Real-Time-PCR array identified decreased expression of several pro-angiogenic secreted factors such as EphrinA1, FGF-2, and VEGF-A upon β-catenin inhibition in liver tumor cells. Conversely, transfection of stabilized-β-catenin mutants enhanced the expression of angiogenic factors like VEGF-A. Conditioned media from HepG2 cells treated with β-catenin but not the mismatch γGPNA significantly diminished spheroid and tubule formation by SK-Hep1 cells, an HCC-associated endothelial cell line. Thus, we report a novel class of cell permeable and efficacious γGPNAs that effectively targets β-catenin, a known oncogene in the liver. Our study also identifies a novel role of β-catenin in liver tumor angiogenesis through paracrine mechanisms in addition to its roles in proliferation, survival, metabolism and cancer stem cell biology, thus further strengthening its effectiveness as a therapeutic target in HCC.
β-Catenin; Wnt signaling; liver cancer; angiogenesis; proliferation and antisense
We have shown previously that withaferin A (WA), which is a highly promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits viability of cultured breast cancer cells in association with reactive oxygen species (ROS)-dependent apoptosis induction. Because ROS production is implicated in induction of autophagy, which is an evolutionary conserved process for bulk degradation of cellular components including organelles (e.g., mitochondria) and considered a valid cancer chemotherapeutic target, we questioned whether WA treatment resulted in autophagy induction. Indeed exposure of MDA-MB-231 and MCF-7 human breast cancer cells as well as a spontaneously immortalized and non-tumorigenic normal human mammary epithelial cell line (MCF-10A) to pharmacologic concentration of WA resulted in autophagy as evidenced by transmission electron microscopy, cleavage of microtubule-associated protein 1 light chain 3 isoform B (LC3B-II), and/or acridine orange staining. Inhibition of MDA-MB-231 xenograft growth in vivo by WA administration was also associated with a significant increase in level of total LC3 protein in the tumor. However, WA-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was not compromised either by pharmacological suppression of autophagy using 3-methyl adenine or genetic repression of autophagy by RNA interference of Atg5, a critical component of the autophagic machinery. Finally, Beclin1 was dispensable for WA-mediated autophagy as well as inhibition of MDA-MB-231 cell viability. Based on these observations we conclude that autophagy induction fails to have any meaningful impact on WA-mediated lethality in breast cancer cells, which may be a therapeutic advantage because autophagy serves to protect against apoptosis by several anticancer agents.
Withaferin A; Breast Cancer; MDA-MB-231; MCF-7; Autophagy; Atg5; Beclin1
The aryl hydrocarbon receptor (AhR) is a ligand activated basic helix-loop-helix transcription factor that binds to environmental poly aromatic hydrocarbons (PAH) and mediates their toxic and carcinogenic responses. There is ample documentation for the role of AhR in PAH-induced carcinogenicity. However, in this report we addressed whether overexpression of AhR alone is sufficient to induce carcinogenic transformation in human mammary epithelial cells (HMEC). Retroviral expression vectors were used to develop a series of stable cell lines expressing varying levels of AhR protein in an immortalized normal HMEC with relatively low endogenous AhR expression. The resulted increase in AhR expression and activity correlated with the development of cellular malignant phenotypes, most significantly epithelial-to-mesenchymal transition. Clones overexpressing AhR by more than 3-fold, exhibited a 50% decrease in population doubling time. Cell cycle analysis revealed that this increase in proliferation rates was due to an enhanced cell cycle progression by increasing the percentage of cells transiting into S- and G2/M phases. Cells overexpressing AhR exhibited enhanced motility and migration. Importantly, these cells acquired the ability to invade matrigel matrix, where more than 80% of plated cells invaded the matrigel matrix within 24 h, whereas none of parental or the vector control HMEC were able to invade matrigel. Collectively, these data provide evidence for a direct role of AhR in the progression of breast carcinoma. The results suggest a novel therapeutic target that could be considered for treatment and prevention of breast cancer progression.
aryl hydrocarbon receptor; ectopic overexpression; mammary epithelia; transformation; breast cancer; progression
Tumor microenvironment (TME) refers to the dynamic cellular and extra-cellular components surrounding tumor cells at each stage of the carcinogenesis. TME has now emerged as an integral and inseparable part of the carcinogenesis that plays a critical role in tumor growth, angiogenesis, epithelial to mesenchymal transition (EMT), invasion, migration and metastasis. Besides its vital role in carcinogenesis, TME is also a better drug target because of its relative genetic stability with lesser probability for the development of drug-resistance. Several drugs targeting the TME (endothelial cells, macrophages, cancer-associated fibroblasts, or extra-cellular matrix) have either been approved or are in clinical trials. Recently, non-steroidal anti-inflammatory drugs targeting inflammation were reported to also prevent several cancers. These exciting developments suggest that cancer chemopreventive strategies targeting both tumor and TME would be better and effective towards preventing, retarding or reversing the process of carcinogenesis. Here, we have reviewed the effect of a well established hepatoprotective and chemopreventive agent silibinin on cellular (endothelial, fibroblast and immune cells) and non-cellular components (cytokines, growth factors, proteinases etc.) of the TME. Silibinin targets TME constituents as well as their interaction with cancer cells, thereby inhibiting tumor growth, angiogenesis, inflammation, EMT, and metastasis. Silibinin is already in clinical trials, and based upon completed studies we suggest that its chemopreventive effectiveness should be verified through its effect on biological end points in both tumor and TME. Overall, we believe that the chemopreventive strategies targeting both tumor and TME have practical and translational utility in lowering the cancer burden.
Angiogenesis; Chemoprevention; Inflammation; Metastasis; Silibinin; Tumor microenvironment
Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years.
Acute Myeloid Leukemia; novel drugs; emerging agents
Because activated oncogenes like Ras have traditionally been thought as promoting unrestrained proliferation, the concept of oncogene-induced senescence has been, and still is, controversial. The counter-intuitive notion that activation of oncogenes leads to the prevention of cellular proliferation has initially been fueled by in vitro studies using ectopic expression of activated Ras in primary fibroblasts. While these initial studies demonstrated unambiguously the existence of a new type of cellular senescence, induced by oncogenes in an ex-vivo system, questions were raised about the physiological relevance of this process. Indeed, recent technical advances in mouse modeling for cancer have suggested that the occurrence of Ras-induced senescence is highly dependent on the cellular context, as well as the level of expression of activated Ras, and may not be pertinent to the study of human cancer initiation and/or progression. However, our increased knowledge of the molecular basis for cellular senescence has led to a better understanding of the molecular events modulating cancer progression in vivo. Recent studies have not only clearly established the incidence of cellular senescence in pre-neoplasic lesions, but also its role as a potential tumor-suppressor mechanism in vivo. Here, we review the recent and exciting new findings regarding the physiological relevance of Ras-induced senescence, and discuss their implications in terms of cancer therapy.
Senescence; cell cycle; cancer; chromatin; Rb; SAHF; SASP
Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immotile epithelial cells lose adherent and tight junctions, and become migratory mesenchymal cells. As a key transcriptional repressor of E-cadherin expression in EMT, Snail plays an important role in embryonic development and cancer progression. Emerging evidences indicate that Snail confers tumor cells with cancer stem cell-like traits, and promotes drug resistance, tumor recurrence and metastasis. In this review, we summarize recent developments underlying the regulation and functions of Snail in tumor progression, and discuss new approaches against EMT in preventing metastatic cancers.
Breast cancer; EMT; metastasis; signaling pathway; Snail
Epithelial to mesenchymal transition (EMT) is an important and complex phenomenon that determines the aggressiveness of cancer cells. The morphological transformation of cancerous cells is accompanied by various cellular processes such as alterations in cell-cell adhesion, cell matrix degradation, down regulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin. Besides these markers several other important tumor antigens/mucins are also involved in the EMT process. Mainly high molecular weight glycoproteins such as mucin molecules (MUC1, MUC4 and MUC16) play a major role in the cellular transformation and signaling alteration in EMT process. In addition to these factors, EMT may be an essential process triggering the emergence or expansion of the CSC population, which slowly results in the initiation of tumor at metastatic sites. Furthermore, mucins have been demonstrated to be involved in the EMT process and also in the enrichment of cancer stem cell population. Mucin mediated EMT is very complex since the key components of tumor microenvironment are also regulating mucin molecules. In this review, we have discussed all the aforementioned factors and their mechanistic involvement for EMT process.
EMT transcription factors; EMT signaling; Mucins; MUC1; MUC4; MUC16; Cancer stem cells; Tumor microenvironment
The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.
Hepatocellular carcinoma (HCC) is a common malignancy that affects a large number of patients worldwide, with an increasing incidence in the United States and Europe. The therapies that are currently available for patients with inoperable HCC have limited benefits. Although molecular targeted therapies against selected cell signaling pathways have shown some promising results, their impact has been minimal. There is a need to identify and explore other targets for the development of novel therapeutics. Several non-protein coding RNAs (ncRNA) have recently been implicated in hepatocarcinogenesis and tumor progression. These ncRNA genes represent promising targets for cancer. However, therapeutic targeting of ncRNA genes has not been employed for HCC. The use of antisense oligonucleotides and viral vector delivery approaches has been shown to be feasible approaches to modulate ncRNA expression. HCC is an optimal cancer to evaluate novel RNA based therapeutic approaches because of the potential of effective delivery and uptake of therapeutic agents to the liver. In this review, we discuss selected ncRNA that could function as potential targets in HCC treatment and outline approaches to target ncRNA expression. Future challenges include the need to achieve site-specific targeting with acceptable safety and efficacy.
Antagomirs; HCC; LNA-antimiR; miRNA; non-coding RNA; ultraconserved
The human HtrA family of serine proteases consists of four members: HtrA1, HtrA2, HtrA3 and HtrA4. Although prokaryotic HtrA proteins are well characterized in their dual roles as chaperones and proteases that degrade misfolded proteins in the periplasm, some members of mammalian HtrA proteins are described as potential modulators of programmed cell death and chemotherapy-induced cytotoxicity. Goal of this review article is to describe the molecular alterations associated with these HtrA serine proteases and how these alterations may be associated with tumor behavior and response to chemotherapy. We will also discuss evidence that chemotherapeutic drugs regulate the expression and activation of HtrA serine proteases and that these proteases contributes to programmed cell death. Finally, we will discuss the potential role of epigenetic therapy in targeting the expression and activation of HtrA serine proteases and the mechanisms by which these proteases enhance cytotoxic effect of conventional chemotherapy.
The purpose of this study was to determine the effects of the histone deacetylase inhibitor, MS-275, on the Fas signaling pathway and susceptibility of osteosarcoma (OS) to Fas ligand (FasL)-induced cell death. OS metastasizes almost exclusively to the lungs. We have shown that Fas expression in OS cells is inversely correlated with their metastatic potential. Fas+ cells are rapidly eliminated when they enter the lungs via interaction with FasL, which is constitutively expressed in the lungs. Fas− OS cells escape this FasL-induced apoptosis and survive in the lung microenvironment. Moreover, upregulation of Fas in established OS lung metastases results in tumor regression. Therefore, agents that upregulate Fas expression or activate the Fas signaling pathway may have therapeutic potential. Treatment of Fas− metastatic OS cell lines with 2 μM MS-275 sensitized cells to FasL-induced cell death in vitro. We found that MS-275 did not alter the expression of Fas on the cell surface; rather it resulted in the downregulation of the anti-apoptotic protein, c-FLIP (cellular FLICE-inhibitory protein), by inhibiting c-FLIP mRNA. Downregulation of c-FLIP correlated with caspase activation and apoptosis induction. Treatment of nu/nu-mice with established OS lung metastases with oral MS-275 resulted in tumor regression, increased apoptosis and a significant inhibition of c-FLIP expression in tumors. Histopathological examination of mice showed no evidence of significant toxicity. Overall, these results suggest that the mechanism by which MS-275 sensitizes OS cells and lung metastases to FasL-induced cell death may be by a direct reduction in the expression of c-FLIP.
c-FLIP; Fas; FasL; histone deacetylase inhibitors; MS-275; Entinostat; osteosarcoma
Epigenetics play a critical role in controlling normal gene expression and altered epigenetics can lead to abnormal cellular differentiation, proliferation and survival. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and is characterized by numerous epigenetic abnormalities. These epigenetic changes correspond to repressed activity of some genes and inappropriate activation of others. In contrast to genetic alterations stemming from mutations, deletions or translocation, epigenetic changes are relatively reversible when treated with certain small molecule-based anticancer agents. Histone deacetylase inhibitors (HDI) are a class of drugs capable of modifying the epigenetic status of ALL cells. Several recent preclinical and clinical studies have demonstrated the potential of HDI as therapeutic agents in ALL. This review summarizes recent studies on (1) the principles of epigenetics and their importance in ALL tumorigenesis; (2) the structure, mechanism of action and anti-tumor activity of HDI; (3) the first comprehensive summary of data from preclinical and clinical studies for HDI as the therapeutic agents for ALL; and (4) novel directions for future research on HDI and ALL.
PMID: 21762078 CAMSID: cams3770
Leukemia; epigenetics; histone deacetylase inhibitors; therapeutic agent; anticancer agent; small molecule inhibitors
The present study is the first to show in pancreatic cancer (PC) the growth inhibition and apoptosis by novel MDM2 inhibitors (MI-319 & 219) through reactivation of p53 pathway. Our results highlight two new secondary targets of MDM2 inhibitor ‘SIRT1’ and Ku70. SIRT1 has a role in ageing and cancer and is known to regulate p53 signaling through acetylation. Ku70 is a key component of non-homologous end joining machinery in the DNA damage pathway and is known to regulate apoptosis by blocking Bax entry into mitochondria. Given the growth inhibition and apoptosis by MI-219, MI-319 was accompanied by increase in levels of p53 along with p21WAF1 and the proapoptotic Puma. SiRNA against p21WAF1 abrogated the growth inhibition of PC cells confirming p21WAF1 as a key player downstream of activated p53. Immunoprecipitation-western blot analysis revealed reduced association of MDM2-p53 interaction in drug exposed PC cells. In combination studies, the inhibitors synergistically augmented anti-tumor effects of therapeutic drug gemcitabine both in terms of cell growth inhibition as well as apoptosis. Surface plasmon resonance studies confirmed strong binding between MI-319 and Ku70 (KD 170 nM). Western blot revealed suppression of SIRT1 and Ku70 with simultaneous upregulation of acetyl-p53 (Lys379) and Bax. Co-Immunoprecipitation studies confirmed that MI-319 could disrupt Ku70-Bax and SIRT1-Bax interaction. Further, using wt-p53 xenograft of Capan-2, we found that oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals. No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment.
MDM2 and p53; Small molecule inhibitors; cell cycle arrest; apoptosis; pancreatic cancer
Inorganic arsenic is an environmental human carcinogen, and has been shown to act as a co-carcinogen with solar ultraviolet (UV) radiation in mouse skin tumor induction even at low concentrations. However, the precise mechanism of its co-carcinogenic action is largely unknown. Apoptosis plays an essential role as a protective mechanism against neoplastic development in the organism by eliminating genetically damaged cells. Thus, suppression of apoptosis is thought to contribute to carcinogenesis. It is known that cyclooxygenase-2 (COX-2) can promote carcinogenesis by inhibiting cell apoptosis under stress conditions; and our current studies investigated the potential contribution of COX-2 to the inhibitory effect of arsenite in UV-induced cell apoptosis in mouse epidermal Cl41 cells. We found that treatment of cells with low concentration (5 μM) arsenite attenuated cellular apoptosis upon UVB radiation accompanied with a co-inductive effect on COX-2 expression and nuclear factor-κB (NFκB) transactivation. Our results also showed that the COX-2 induction by arsenite and UVB depended on an NFκB pathway because COX-2 co-induction could be attenuated in either p65-deficient or p50-deficient cells. Moreover, UVB-induced cell apoptosis could be dramatically reduced by the introduction of exogenous COX-2 expression, whereas the inhibitory effect of arsenite on UVB-induced cell apoptosis could be impaired in COX-2 knockdown Cl41 cells. Our results indicated that COX-2 mediated the anti-apoptotic effect of arsenite in UVB radiation through an NFκB-dependent pathway. Given the importance of apoptosis evasion during carcinogenesis, we anticipated that COX-2 induction might be at least partially responsible for the co-carcinogenic effect of arsenite on UVB-induced skin carcinogenesis.
Apoptosis; arsenite; COX-2; NF-κB; UVB
Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice.
Animal model; chemoprevention; clinical trial; hepatocellular carcinoma; liver cirrhosis; prevention
The growth arrest and DNA damage-inducible 45 (Gadd45) proteins are a group of critical signal transducers that are involved in regulations of many cellular functions. Accumulated data indicate that all three Gadd45 proteins (i.e., Gadd45α, Gadd45β, and Gadd45γ) play essential roles in connecting an upstream sensor module, the transcription Nuclear Factor-κB (NF-κB), to a transcriptional regulating module, mitogen-activated protein kinase (MAPK). This NF-κB-Gadd45(s)-MAPK pathway responds to various kinds of extracellular stimuli and regulates such cell activities as growth arrest, differentiation, cell survival, and apoptosis. Defects in this pathway can also be related to oncogenesis. In the first part of this review, the functions of Gadd45 proteins, and briefly NF-κB and MAPK, are summarized. In the second part, the mechanisms by which Gadd45 proteins are regulated by NF-κB, and how they affect MAPK activation, are reviewed.
GADD45α; Gadd45β; Gadd45γ; NF-κB; JNK; P38; Cell survival and apoptosis
Although Bid is considered to be a cell apoptotic mediator, current studies suggest that it has a possible role in cell survival for mouse embryonic fibroblasts (MEFs) in response to low doses of anti-(±)-5- methylchrysene-l,2-diol-3,4-epoxide (<0.25µM) (5-MCDE). We found that the exposure of MEFs to 0.25 µM 5-MCDE resulted in a slight apoptotic induction, while this apoptotic response was substantially increased in the Bid knockout MEFs (Bid−/−), suggesting that there is a Bid-mediated anti-apoptotic function in this response. This notion was further supported by the findings that re-constitution expression of Bid into Bid−/− cells could inhibit the increased apoptosis. Further studies show that the antiapoptotic function of Bid was associated with its mediation of COX-2 expression. This conclusion was based the reduction of COX-2 expression in Bid−/− cells, the restoration of low sensitivity to 5-MCDE-induced apoptosis by the introduction of Bid into Bid−/− cells, and increased sensitivity of WT MEFs to 5-MCDE-induced apoptosis by the knockdown of COX-2 expression. Furthermore, we found that Bid mediated COX-2 expression through the IKKβ/NFκB pathway because the deficiency of Bid in Bid−/− MEFs resulted in the blockade of IKK/NFκB activation and knockout of IKKβ caused abrogation of COX-2 expression induced by 5-MCDE. Collectively, our results demonstrate that Bid is critical for COX-2 induction through the IKKβ/NFκB pathway, which mediates its anti-apoptotic function, in cell response to low doses of 5-MCDE exposure.
Bid; COX-2; 5-MCDE; NFκB; apoptosis