alphavbeta6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor
Program in Molecular Medicine; Department of Radiation Oncology; Department of Pathology; UMass Metabolic Network
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology | Neoplasms | Oncology
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 alphavbeta6 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 alphavbeta6 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 alphavbeta6 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 alphavbeta6 expression. This pathway, which is specific for alphavbeta6, because it is not regulated by a different alphav-containing integrin, alphavbeta3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of alphavbeta6-expressing cells. Consistently, both alphavbeta6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by alphavbeta6 expression. In conclusion, we show that alphavbeta6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the alphavbeta6 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 alphavbeta6 antagonists for prostate cancer therapy.
DOI of Published Version
Cancer Res. 2016 Sep 1;76(17):5163-74. doi: 10.1158/0008-5472.CAN-16-0543. Epub 2016 Jul 22. Link to article on publisher's site
Lu, Huimin; Wang, Tao; Jiang, Zhong; Davis, Roger J.; Fitzgerald, Thomas J.; and Languino, Lucia R., "alphavbeta6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor" (2016). Davis Lab Publications. 86.