Host- versus cell-dependent effects of β-Arrestin 1 expression in prostate tumorigenesis

Abstract

Abstract 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 is androgen independent resulting in lack of response to androgen deprivation therapy. The scaffold proteins β-arrestin 1 and 2 (βarr1 and βarr2) which are known to mediate G protein-coupled receptors (GPCRs) desensitization and internalization, were also shown to modulate prostate tumorigenesis. βarr1 is overexpressed (~4 fold) in PCa cells relative to βarr2. In this study, we investigate the effect of β-arrestins expression in prostate tumorigenesis using in-vivo xenografts and autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model deficient in β-arrestins expression. Depletion of βarr1 in TRAMP mice (TRAMP/βarr1−/−) increased PCa growth and decreased overall survival, relative to TRAMP and TRAMP/βarr2−/− animals. Tumors from TRAMP/βarr1−/− mice displayed increase androgen receptor (AR), but decrease prostate specific antigen (PSA) expression. In contrast, depletion of βarr1 in MDA PCa 2b cells (MDA PCa 2b-βarr1−/−) decreased cell proliferation, wound closure and anchorage independent cell growth compared to wild type MDA PCa 2b and MDA PCa 2b-βarr2−/− cells. Nude mice xenografts of MDA PCa 2b-βarr1−/− cells also showed significant decrease in tumor growth. Interestingly, tumor lysates from MDA PCa 2b-βarr1−/− xenografts exhibited decrease AR and increase PSA expression, relative to control tumors. Altogether, the data indicate that βarr1 modulates AR/PSA signaling to regulate prostate cancer aggressiveness. However, the effect of βarr1 is context-sensitive depending on its expression in the host relative to the tumor cells.