The androgen receptor induces integrin ?6?1 to promote prostate tumor cell survival via NF-?B and Bcl-xL Independently of PI3K signaling.

ABSTRACT: 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 ?6?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 ?6?1 mRNA transcription and protein expression. Subsequent signaling by integrin ?6?1 in AR-expressing cells increased NF-?B activation and Bcl-xL expression. Blocking AR, integrin ?6, NF-?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/?6?1 and PI3K pathways may effectively trigger prostate cancer cell death, enhancing the potential therapeutic value of PI3K inhibitors being evaluated in this setting.

SUBMITTER: Lamb LE 

PROVIDER: S-EPMC6878780 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature