BERKELEY, CA (UroToday.com) - Prostate cancer is the second leading cause of cancer-related death among men in the United States. Although androgen deprivation therapy is an effective treatment during the early stages of prostate cancer, due to the uncertainty in the molecular mechanisms leading to advanced stages of the disease, patients with castration-resistant prostate cancer are left with limited treatment options. Studies in our laboratory over the last several years have demonstrated the integral role of Akt pathway in prostate cancer. Whereas Akt is known to phosphorylate a plethora of substrates, exact functions of Akt and the identity of its entire spectrum of substrates is far from reality. Nevertheless, two-gene family of glycogen synthase kinase-3 (GSK-3α and GSK-3β) is considered one of the best known substrate of Akt, but are still less investigated for its role in physiology and pathology. Due to the indispensable role of Akt in cancer and activity inhibiting GSK-3 phosphorylation by Akt at its Serine 21/9 residue, suppression of GSK-3 activity in cancer cells was always assumed to be a tumor-promoting event. However, recent studies in clinical prostate cancer samples reported increased expression of both GSK-3 isoforms in aggressive prostate cancer tissues, and challenged existing views on the role of GSK-3 on prostate cancer progression.
Currently, it is unclear how both GSK-3 and Akt that inhibits GSK-3 are concurrently maintained active in prostate cancer cells. We hypothesized that GSK-3 activity is preserved in aggressive prostate cancer cells in an Akt independent manner. Our study demonstrated that Src kinase-mediated phosphorylation of GSK-3 tyrosine-216 (Y216GSK-3) residue is important for its activation and mediates prostate cancer cellular function in vitro and tumor growth in vivo. Inhibition of GSK-3 activity as a result of treatment with GSK-3 specific inhibitor SB415286 or RNA interference in murine TRAMP (TR-C2N) and human (PC3) invasive prostate cancer cell lines lead to impaired prostate cancer cell motility, proliferation, survival, invasion, and colony formation in vitro. While expression of PC3 cells with constitutively active cSrc (CA-Src) resulted in enhanced Y216GSK-3 phosphorylation, reduced Y216GSK-3 phosphorylation was observed by expression with kinase dead Src (KD-Src). Analysis of SYF mouse embryonic fibroblasts that are deficient in cSrc, Yes and Fyn showed that even in normal cells, Src deficiency is correlated with reduced Y216GSK-3 phosphorylation. Reconstituting Src activity by expression with CA-Src in SYF cells significantly restored Y216GSK-3 phosphorylation, once again indicating that Y216GSK-3 is a target of Src activity. Treatment of PC3 cells with dasatinib, an inhibitor of SFKs and Bcr/Abl, but not with docetaxel, resulted in reduced phosphorylation of Y416Src and Y216GSK-3. Even though treatment with dasatinib did not significantly induce apoptosis in PC3 cells, this treatment resulted in significant impairment in cell motility, proliferation, and micrometastasis. Furthermore, treatment with dasatinib resulted in decreased Y416Src and Y216GSK-3 phosphorylation, reduced rate of cell proliferation, and growth of PC3 tumor xenograft in an athymic nude mouse model. Together, we demonstrate a novel mechanism of GSK-3 activity regulation in normal and cancer cells with its specific role in prostate cancer progression and reveal the potential benefits of targeting Src-GSK-3 axis using drugs such as dasatinib for prostate cancer therapy
Written by:
Somanath P.R. Shenoy, PhD, FAHA as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Associate Professor, Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia; Charlie Norwood VA Medical Center; Department of Medicine, Cancer Center and Vascular Biology Center, Georgia Regents University, Augusta, GA USA
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