The Androgen Receptor Induces Integrin α6β1 to Promote Prostate Tumor Cell Survival via NF-κB and Bcl-xL Independently of PI3K Signaling

Recent studies indicate that androgen receptor (AR) signaling is critical for prostate cancer cell survival, even in castration-resistant disease wherein AR continues to function independently of exogenous androgens. Integrin-mediated adhesion to the extracellular matrix is also important for prostate cell survival. AR-positive prostate cancer cells express primarily integrin alpha 6 beta 1 and adhere to a laminin-rich matrix. In this study, we show that active nuclear-localized AR protects prostate cancer cells from death induced by phosphoinositide 3-kinase (PI3K) inhibition when cells adhere to laminin. Resistance to PI3K inhibition is mediated directly by an AR-dependent increase in integrin alpha 6 beta 1 mRNA transcription and protein expression. Subsequent signaling by integrin alpha 6 beta 1 in AR-expressing cells increased NF-kappa B activation and Bcl-xL expression. Blocking AR, integrin alpha 6, NF-kappa B, or Bcl-xL concurrent with inhibition of PI3K was sufficient and necessary to trigger death of laminin-adherent AR-expressing cells. Taken together, these results define a novel integrin-dependent survival pathway in prostate cancer cells that is regulated by AR, independent of and parallel to the PI3K pathway. Our findings suggest that combined targeting of both the AR/alpha 6 beta 1 and PI3K pathways may effectively trigger prostate cancer cell death, enhancing the potential therapeutic value of PI3K inhibitors being evaluated in this setting. Cancer Res; 71(7); 2739-49. (C)2011 AACR.