The Androgen Receptor Induces Integrin α6β1 to Promote Prostate Tumor Cell Survival via NF-κB 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 a6b1 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 ARdependent increase in integrin a6b1 mRNA transcription and protein expression. Subsequent signaling by integrin a6b1 in AR-expressing cells increased NF-kB activation and Bcl-xL expression. Blocking AR, integrin a6, NF-kB, or Bcl-xL concurrent with inhibition of PI3K was sufficient and necessary to trigger death of lamininadherent 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/a6b1 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);

β4 Integrin signaling induces expansion of prostate tumor progenitors

“…Since AR signaling suppresses the expression of β4, c-Met, and ErbB2 (84, 85), androgen withdrawal experiments have suggested that focal adhesion kinase, which is activated by multiple β1 integrins, promotes the expansion of tumor progenitor cells in mouse models of mammary and intestinal tumorigenesis (73)(74)(75). Finally, although not directly focusing on tumor progenitor cells, prior studies have emphasized a role for β1 integrins, but not for β4, in prostate cancer (37,(76)(77)(78)(79). Our observation that β4 signaling is dispensable for prostate development but not tumorigenesis is consistent with the hypothesis that tumor cells are exquisitely dependent on certain integrin signaling pathways, such as those activated by β4, whereas their normal counterpart are not (32,74).…”

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

“…Whether a pharmacological strategy would result in such pathologies occurring during development is uncertain but will need to be tested. Future studies might also highlight a potential net benefit of targeting other cellular pools of this integrin, since some of them, notably those expressed on endothelial or tumor cells, also actively participate in cancer progression (22)(23)(24)(25)(26)(27).…”

“…Integrin α6β1, which is expressed on cancer and endothelial cells, has been described to favor tumor angiogenesis, invasiveness, and cancer progression (22)(23)(24)(25)(26)(27). Besides laminins, this integrin has also been reported to bind ADAM9/meltrin-γ, a member of the a disintegrin and metalloproteinase (ADAM) family of proteins (28,29).…”

Identification of Androgen Receptor and Beta-Catenin Target Genes in Prostate and Prostate Cancer

“…There was a greater loss of adhesion in LNCaP than in C4-2 cells. Cell adhesion to matrix is required for cell survival of most epithelial cells, including in prostate and prostate cancer cells (8,9). To determine if the cells were dying, both adherent and non-adherent cells were collected and stained with Trypan Blue.…”