Host- Versus Cell-Dependent Effects Of Beta-Arrestin 1 Expression In Prostate Tumorigenesis

Prostate cancer (PCa) constitutes a serious health challenge and remains one of the main causes of cancer-related death among men. The more aggressive form of the disease has been attributed to androgen independence, resulting in a lack of response to androgen deprivation therapy and sustained activation of other growth pathways. The scaffold proteins beta-arrestin 1 and 2 (beta arr1 and beta arr2), which are known to mediate G protein-coupled receptor desensitization and internalization, were also shown to modulate prostate tumorigenesis. beta arr1 is significantly overexpressed (>4-fold) in PCa cells relative to beta arr2. In this study, we investigated the effect of beta arr1 overexpression in PCa development and progression using the mouse and human PCa cell xenografts, and autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) models deficient in beta-arrestin depletion of beta arr1 in TRAMP mice (TRAMP/beta arr2(-/-)) increased PCa growth and decreased overall survival relative to control TRAMP or TRAMP/beta arr2(-/-) animals. Prostate tissues from TRAMP/beta arr2(-/-) tumors displayed an increase in androgen receptor (AR) expression, whereas overexpression of beta arr1 in TRAMP-C1 (TRAMP-C1-beta arr1-GFP) which derived from TRAMP decreased AR expression, cell proliferation and tumor growth in nude mice xenografts, relative to control TRAMP-C1-GFP. Knockdown of beta arr1 expression in human MDA PCa 2b cells (MDA PCa 2b-beta arr2(-/-)) also decreased AR expression cell proliferation and tumor growth relative to control (MDA PCa 2b-Sham) cells. Interestingly, both TRAMP-C1-beta arr1-GFP and MDA PCa 2b-beta arr1(-/-) xenografts showed a decrease in AKT phosphorylation but an increase in MAPK activation. Altogether, the data indicate that the effect of beta arr1 in modulating AR signaling to regulate PCa aggressiveness is cell and host autonomous.