Survival Signaling in Prostate Cancer: Role of Androgen Receptor and Integrins in Regulating Survival
Annual summary 1 Jan 2008-31 Dec 2010
VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI
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Although prostate cancer patients initially respond to androgen ablation therapy, they ultimately relapse and the tumor no longer responds to androgen, offering little hope for long-term disease-free survival. However, inhibition of AR expression in cells leads to cell death. This suggests that prostate cancer cells are still dependent on AR for survival, even if the cells are no longer responding to physiological levels of androgen. We have demonstrated that expression of AR in PC3 prostate tumor cells can rescue cells from death induced by inhibition of PI3K. Expression of AR in PC3 cells leads to increased expression of integrin alpha6beta1 and Bcl-xL along with increased activation of NF-kappaB. Blocking each these components individually concurrent with inhibition of PI3K led to death of the AR-expressing cells, suggesting that AR regulates cell survival through enhancement of alpha6beta1NF-kappaBBcl-xL signaling. We have also confirmed that this pathway is activated in prostate cancer cell lines expressing endogenous AR, including LNCaP, C4-2 and VCaP cells.
- Medicine and Medical Research