The androgen receptor induces integrin α6β1 to promote prostate tumor cell survival via NF-κB and Bcl-xL Independently of PI3K signaling

Cancer Res. 2011 Apr 1;71(7):2739-49. doi: 10.1158/0008-5472.CAN-10-2745. Epub 2011 Feb 10.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / physiology
  • Humans
  • Integrin alpha6beta1 / biosynthesis*
  • Integrin alpha6beta1 / genetics
  • Male
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction
  • Transcription, Genetic
  • Transfection
  • Up-Regulation
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • BCL2L1 protein, human
  • Integrin alpha6beta1
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • Receptors, Androgen
  • bcl-X Protein