Alpha V Beta 6 Integrin Promotes Castrate-Resistant Prostate Cancer Through Jnk1-Mediated Activation Of Androgen Receptor

Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Pten(pc-/-), carrying a prostate epithelial-specific Pten deletion, we show that the alpha v beta 6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the alpha v beta 6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by alpha v beta 6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by alpha v beta 6 expression. This pathway, which is specific for alpha v beta 6, because it is not regulated by a different alpha v-containing integrin, alpha v beta 3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of alpha v beta 6 expressing cells. Consistently, both alpha v beta 6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by alpha v beta 6 expression. In conclusion, we show that alpha v beta 6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the alpha v beta 6 integrin causes androgen receptor-increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of alpha v beta 6 antagonists for prostate cancer therapy. (C) 2016 AACR.