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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 α6β1 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 α6β1 mRNA transcription and protein expression. Subsequent signaling by integrin α6β1 in AR-expressing cells increased NF-κB activation and Bcl-xL expression. Blocking AR, integrin α6, NF-κB, 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/α6β1 and PI3K pathways may effectively trigger prostate cancer cell death, enhancing the potential therapeutic value of PI3K inhibitors being evaluated in this setting.

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