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1.  Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K/Akt/NF-κB 
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of death in males in the United States. Using human prostate cancer specimens, the authors have previously shown that elevated expression levels of 12-lipoxygenase (12-LOX) occurred more frequently in advanced stage, high-grade prostate cancer, suggesting that 12-LOX expression is associated with carcinoma progression and invasion. Previous reports from their group and others have shown that 12-LOX is a positive modulator of invasion and metastasis; however, the mechanism remains unclear. In this work, a new link between 12-LOX and the matrix metalloproteinase 9 (MMP9) in prostate cancer angiogenesis is reported. This study demonstrated that overexpression of 12-LOX in prostate cancer PC-3 cells resulted in elevated expression of MMP9 mRNA, protein and secretion. Exogenous addition of 12(S)-hydroxy eicosatetraenoic acid, the sole and stable end product of arachidonic acid metabolism by 12-LOX, is able to increase MMP9 expression in wild-type PC-3 cells. Furthermore, using pharmacological and genetic inhibition approaches, it was found that 12-LOX activates phosphoinositol 3 kinase (PI3K)/Akt, which results in nuclear factor-kappa B (NF-κB)-driven MMP9 expression, ensuing in enhanced chemoattraction of endothelial cells. Specific inhibitors of 12-LOX, PI3K or NF-κB inhibited MMP9 expression in 12-LOX-expressing PC-3 cells and resulted in the blockade of the migratory ability of endothelial cells. In summary, the authors have identified a new pathway by which overexpression of 12-LOX in prostate cancer cells leads to augmented production of MMP9 via activation of PI3K/Akt/NF-κB signaling. The role of 12-LOX-mediated MMP9 secretion in endothelial cell migration may account for the proangiogenic function of 12-LOX in prostate cancer.
doi:10.1002/ijc.28165
PMCID: PMC4269488  PMID: 23526143
12-lipoxygenase; matrix metalloproteinase; MMP9; NF-κB; prostate cancer; angiogenesis
2.  Platelets and cancer: a casual or causal relationship: revisited 
Cancer metastasis reviews  2014;33(1):231-269.
Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate the production circulating platelets. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. The most critical biological platelet response is serving as “First Responders” during the wounding process. The exposure of extracellular matrix proteins and intracellular components occurs after wounding. Numerous platelet receptors recognize matrix proteins that trigger platelet activation, adhesion, aggregation, and stabilization. Once activated, platelets change shape and degranulate to release growth factors and bioactive lipids into the blood stream. This cyclic process recruits and aggregates platelets along with thrombogenesis. This process facilitates wound closure or can recognize circulating pathologic bodies. Cancer cell entry into the blood stream triggers platelet-mediated recognition and is amplified by cell surface receptors, cellular products, extracellular factors, and immune cells. In some cases, these interactions suppress immune recognition and elimination of cancer cells or promote arrest at the endothelium, or entrapment in the microvasculature, and survival. This supports survival and spread of cancer cells and the establishment of secondary lesions to serve as important targets for prevention and therapy.
doi:10.1007/s10555-014-9498-0
PMCID: PMC4186918  PMID: 24696047
Platelet; TCIPA; Metastasis; Thrombosis; Extravasation; CTC
3.  Sphingosine-1-phosphate receptor-2 mediated NFκB activation contributes to tumor necrosis factor-α induced VCAM-1 and ICAM-1 expression in endothelial cells 
Prostaglandins & other lipid mediators  2013;0:10.1016/j.prostaglandins.2013.06.001.
Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions in endothelial cells. We previously showed that S1P receptor subtype 2 (S1P2) is significantly up-regulated in the atherosclerotic endothelium (J. Biol. Chem. 283:30363, 2008). In this study, we investigated the roles of S1P2-mediated signaling in the proinflammatory responses of endothelial cells. Treatment with tumor necrosis factor-α (TNFα), a proinflammatory cytokine, increased the expression of S1P2 receptors in endothelial cells. TNFα treatment also enhanced sphingosine kinase 1 expression and increased S1P production. Pharmacological inhibition or knockdown of S1P2 receptors completely abrogated the TNFα-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression in endothelial cells. In contrast, pharmacological inhibition or knockdown of other S1P receptor subtypes had no effect on the TNFα-stimulated ICAM-1 and VCAM-1 expression. Moreover, ectopic expression of S1P2 receptors increased VCAM-1 and ICAM-1 expression in endothelial cells in response to S1P stimulation. Mechanistically, we show that antagonizing S1P2 signaling markedly inhibited the TNFα-stimulated NFκB activation. Utilizing the NFκB reporter luciferase assay, the S1P/S1P2 signaling was shown to stimulate NFκB activation. Moreover, the S1P/S1P2-stimulated VCAM-1/ICAM-1 expression was completely abolished by the pharmacological inhibitor of NFκB. Collectively, our data suggest that TNFα treatment activates autocrine S1P/S1P2 signaling, which subsequently activates NFκB and leads to the proinflammatory responses in endothelial cells.
doi:10.1016/j.prostaglandins.2013.06.001
PMCID: PMC3844125  PMID: 23770055
sphingosine-1-phosphate; S1P family of G-protein coupled receptor; sphingolipids; sphingosine kinase; vasculature
4.  The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis 
Cancer metastasis reviews  2011;30(0):397-408.
Thromboxane A2 (TXA2) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A2 synthase (TXA2S), on prostaglandin endoperoxide (PGH2). TXA2 is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A2 synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A2 is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA2S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA2 as a downstream metabolite of the COX-2-derived PGH2. Several studies suggest potential involvement of TXA2S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA2S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA2S and TP in cancer progression and metastasis.
doi:10.1007/s10555-011-9297-9
PMCID: PMC4175445  PMID: 22037941
Thromboxane synthase; Thromboxane receptor; Cyclooxygenase; Cancer progression; Metastasis; Angiogenesis; Cell migration; Apoptosis
5.  Significance of SHP-1 and SHP-2 Expression in Human Papillomavirus Infected Condyloma acuminatum and Cervical Cancer 
Pathology oncology research : POR  2008;14(4):365-371.
Human papillomaviruses (HPVs) are a group of DNA viruses that infect the skin and mucous membranes. Type HPV6/11 is closely related to Condyloma acuminatum, while HPV16/18 is the principal cause of cervical cancer. In this study, we examined the expression of protein tyrosine phosphatases SHP-1 and SHP-2 in Condyloma acuminatum, cervical cancer and the relationship between SHP-1/SHP2 expression and HPV infection. Forty Condyloma acuminatum cases, 20 cervical cancer cases and 20 normal human foreskins were examined for HPV infection by in situ hybridization and the expression of SHP-1 and SHP-2 were examined by immunohistochemistry. Results demonstrated that positive expression rates of HPV6/11, HPV16/18, and HPV31/33 were 98%, 10%, and 7.5% in Condyloma acuminatum, 10%, 85%, and 25% in cervical cancer. Only one normal foreskin demonstrated positive staining for HPV16/18. Positive expression rates of SHP-1 and SHP-2 were 80% and 85% in Condyloma acuminatum, 85% and 90% in cervical cancer. The SHP-1 and SHP-2 expressions were mainly distributed in the prickle layer of Condyloma acuminatum and were diffusely distributed in cervical cancer cells. Only 35% and 30% of foreskins demonstrated weak staining in the basal layer cells. There were statistically significant correlations among the infection of HPV and the expression of SHP-1 and SHP-2 in both Condyloma acuminatum and cervical cancer (P<0.05). SHP-1 expression has a positive correlation with SHP-2 expression. Our results demonstrate putative roles of SHP-1 and SHP-2 in the progression of both Condyloma acuminatum and cervical cancer after HPV infection.
doi:10.1007/s12253-008-9065-5
PMCID: PMC4175450  PMID: 18543080
Cervical cancer; Condyloma acuminatum; Human papillomavirus; Protein tyrosine phosphatase
6.  Emerging targets in lipid-based therapy☆ 
Biochemical pharmacology  2012;85(5):673-688.
The use of prostaglandins and NSAIDS in the clinic has proven that lipid mediators and their associated pathways make attractive therapeutic targets. When contemplating therapies involving lipid pathways, several basic agents come to mind. There are the enzymes and accessory proteins that lead to the metabolism of lipid substrates, provided through diet or through actions of lipases, the subsequent lipid products, and finally the lipid sensors or receptors. There is abundant evidence that molecules along this lipid continuum can serve as prognostic and diagnostic indicators and are in fact viable therapeutic targets. Furthermore, lipids themselves can be used as therapeutics. Despite this, the vernacular dialog pertaining to “biomarkers” does not routinely include mention of lipids, though this is rapidly changing. Collectively these agents are becoming more appreciated for their respective roles in diverse disease processes from cancer to preterm labor and are receiving their due appreciation after decades of ground work in the lipid field. By relating examples of disease processes that result from dysfunction along the lipid continuum, as well as examples of lipid therapies and emerging technologies, this review is meant to inspire further reading and discovery.
doi:10.1016/j.bcp.2012.11.028
PMCID: PMC4106802  PMID: 23261527
Cancer; Bioactive lipids; Raman; Therapeutics; Biomarkers; Drug synergism
7.  12-LIPOXYGENASE AND THE REGULATION OF HYPOXIA-INDUCIBLE FACTOR IN PROSTATE CANCER CELLS 
Experimental cell research  2010;316(10):1706-1715.
12-lipoxygenase, an arachidonic acid metabolizing enzyme of the lipoxygenase pathway, has been implicated as a major factor in promoting prostate cancer progression and metastasis. The ability of 12-LOX to aggravate the disease was linked to its proangiogenic role. Recent studies clearly demonstrated that 12-LOX enhances the expression and secretion of the angiogenic factor, vascular endothelial growth factor (VEGF) thus providing a direct link between this enzyme and its angiogenic properties. In the present study we have investigated the relationship between 12-LOX and hypoxia inducible factor-1α (HIF-1α), a transcription factor involved in the regulation of VEGF expression under hypoxic conditions in solid tumors. Our findings have revealed that HIF-1 is one of the target transcription factors regulated by 12-LOX and 12(S)-HETE, in hypoxic tumor cells of the prostate. Regulation of HIF-1α by 12-LOX adds to the complexity of pathways mediated by this enzyme in promoting prostate cancer angiogenesis and metastasis. We have evidence that 12-LOX increases the protein level, mRNA, and functional activity of HIF-1α under hypoxic conditions, one of the mechanisms by which it upregulates VEGF secretion and activity.
doi:10.1016/j.yexcr.2010.03.005
PMCID: PMC3420817  PMID: 20303950
12-Lipoxygenase; Hypoxia Inducible Factor-1α (HIF-1α); angiogenesis; prostate cancer; hypoxia
8.  Sphingosine-1-phosphate receptor-3 signaling up-regulates epidermal growth factor receptor and enhances epidermal growth factor receptor-mediated carcinogenic activities in cultured lung adenocarcinoma cells 
International journal of oncology  2012;40(5):1619-1626.
Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions. However, the role of S1P signaling in tumorigenesis remains to be elucidated. In this study, we show that S1P receptor subtype 3 (S1P3) is markedly up-regulated in a subset of lung adenocarcinoma cells compared to normal lung epithelial cells. Specific knockdown of S1P3 receptors inhibits proliferation and anchorage-independent growth of lung adenocarcinoma cells. Mechanistically, we demonstrate that S1P3 signaling increases epidermal growth factor receptor (EGFR) expression via the Rho kinase (ROCK) pathway in lung adenocarcinoma cells. Nuclear run-off analysis indicates that S1P/S1P3 signaling transcriptionally increases EGFR expression. Knockdown of S1P3 receptors diminishes the S1P-stimulated EGFR expression in lung adenocarcinoma cells. Moreover, S1P treatment greatly enhances EGF-stimulated colony formation, proliferation and invasion of lung adenocarcinoma cells. Together, these results suggest that the enhanced S1P3-EGFR signaling axis may contribute to the tumorigenesis or progression of lung adenocarcinomas.
doi:10.3892/ijo.2012.1379
PMCID: PMC3797598  PMID: 22344462
sphingosine-1-phosphate; sphingosine-1-phosphate receptor subtype 3; epidermal growth factor; epidermal growth factor receptor; S1P3; lung carcinoma
9.  Downregulation of Vascular Endothelial Growth Factor and Induction of Tumor Dormancy by 15-lipoxygenase-2 in Prostate Cancer 
The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxyeicosatetraenoic acid (HETE). Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15-LOX-2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15-LOX-2 in prostate cancer, we expressed 15-LOX-2 as a fusion protein with GFP in DU145 and PC-3 cells and found that 15-LOX-2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15-LOX-2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15-LOX-2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15-LOX-2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF-A) was significantly reduced in prostate cancer cells with 15-LOX-2 expression restored. Our studies suggest that 15-LOX-2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15-LOX-2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo.
doi:10.1002/ijc.24118
PMCID: PMC2913418  PMID: 19089921
tumor dormancy; angiogenesis; lipoxygenase; prostate cancer; VEGF

Results 1-9 (9)