TITLE: Survival Signaling in Prostate Cancer: Role of Androgen Receptor and Integrins in Regulating Survival PRINCIPAL INVESTIGATOR:

Poster Presentation: American Association for Cancer Research: “Advances in Prostate Cancer Research”, San Diego, CA, January 21-24. AR-Enhanced α6β1 Integrin and Bcl-xL Expression Promotes Androgen-Independent Prostate Tumor Cell Survival Independently of PI-3K Signaling Laura E. Lamb , Jelani Zarif , and Cindy K. Miranti Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI Cell and Molecular Biology Program, Michigan State University, East Lansing, MI Background: 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 or its DNA binding activity even in androgen independent (i.e. non-responsive) cells inhibits their proliferation and 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. Objective: In prostate cancer, unlike in the normal gland, the tumor epithelial cells expressing AR are adherent to extracellular matrix, allowing for potential interactions between integrins, involved in cell matrix adhesion, and AR. Signaling pathways stimulated by both AR and integrins are known to regulate cell survival. We tested the hypothesis that the interaction of cancer cells with the matrix and the integration of signals from integrins and AR cooperatively regulate their survival. Methods: Androgen receptor expression was restored to near physiological levels in PC3 cells. The signaling pathways that are required for survival of AR-expressing PC3 cells plated on the extracellular matrix laminin were compared to those required for non-AR expressing cells. Results: Survival of PC3 cells adherent to laminin is dependent on PI-3K signaling. Reexpression of wild type AR in PC3 cells prevented the cell death normally induced upon inhibition of PI-3K signaling. Rescue of cell death occurred independently of androgen. Expression of AR in PC3 cells lead to increased expression of the pro-survival protein Bcl-xL and α6β1integrin, and down regulation of other integrins. Loss of AR, integrin α6, or Bcl-xL resensitized AR-expressing PC3 cells to PI-3K-dependent survival. The AR-induced increase in α6 integrin is responsible for the elevated Bcl-xL levels. Thus AR regulates cell survival through enhancement of α6β1 expression, which up-regulates Bcl-xL, independently of PI-3K signaling. We are currently exploring the mechanism by which AR enhances α6β1 expression. Conclusions: AR can support androgen-independent prostate tumor cell survival on laminin via enhanced expression of α6β1 integrin, leading to elevated Bcl-xL levels, by a mechanism that is independent of PI-3K. These findings have significant implications for therapeutic targeting of androgen-independent prostate cancer cells.