Background: Prostate cancer (PC) remains the second leading cause of male death in Western countries and has been on the rise in Qatar during the last decade. Recent studies established that unlike differentiated PC cells, PC stem cells (PCSC) display high tumorigenic and metastatic potential and become resistant to current therapy. Therefore therapeutic success depends on the ability to effectively kill PCSC. The disease progression to advanced stages is attributed to the development of anti-apoptotic signaling mechanisms in cancer cells activated by several growth factors and neuropeptides. Relatively little is known about the survival signaling mechanisms in PCSC. An understanding of the molecular mechanisms involved in the resistance of PCSC to current therapeutic regimens is of immense clinical interest. Objectives: The objectives of this study include the identification in PC stem cells of the anti-apoptotic mechanisms activated by growth factors and neuropeptides that overexpress in advanced PC, and to address how these survival agonists modulate self-renewal of PCSC. Methods: The PCSC were sorted from cancer cell lines and enriched. Apoptosis was induced in PCSC by inhibiting the survival of kinase PI3K using pharmacological inhibitor, LY294002. The cytoprotective and self-renewal effects of growth factors and neuropeptides were assessed. Results: Using stem cell specific markers, we isolated PCSC population (CD44+CD22-) form human PC cell lines, and enriched them by forming prostatospheres using anchorage independent serum free conditions. Treatment with LY induced apoptosis in PCSC, while EGF and vasoactive intestinal peptide (VIP) protected PCSC from apoptosis. We show that the cytotoxic effects of LY are mediated by dephosphorylating a pro-apoptotic BCl-2 family protein BAD, while cytoprotective effects of both EGF and VIP are mediated by inducing re-phosphorylation of BAD. Both EGF and VIP enhanced the self-renewal capacity of PCSC by producing increased numbers of prostatospheres. Conclusions: EGF and VIP not only protect from apoptosis, but also increase self-renewal of PCSC. The BAD seems to act as a signaling node that control both apoptosis and survival, thus qualifies as a better therapeutic target. Attempts are being made to identify mechanisms induced by these survival agonists; and identify the correlation between disease progression and BAD expression/phosphorylation in PC clinical samples.


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