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

Abstract

Prostate cancer 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 lack of response to androgen deprivation therapy and sustained activation of other growth pathways. The scaffold proteins β-arrestin 1 and 2 (βarr1 and βarr2) which are known to mediate G protein-coupled receptor desensitization and internalization, were also shown to modulate prostate tumorigenesis. βarr1 is significantly overexpressed (>4 fold) in prostate cancer cells relative to βarr2. In this study, we investigated the effect of βarr1 overexpression in prostate cancer development and progression using the mouse and human PCa cell xenografts, and autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) models deficient in β-arrestins Depletion of βarr1 in TRAMP mice (TRAMP/βarr1 -/-) increased PCa growth and decreased overall survival relative to control TRAMP or TRAMP/βarr2 -/- animals. Prostate tissues from TRAMP/βarr1 -/- tumors displayed an increase in androgen receptor expression whereas overexpression of βarr1 in TRAMP-C1 (TRAMP-C1-βarr1-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 βarr1 expression in human MDA PCa 2b cells (MDA PCa 2b-βarr1 -/-) also decreased AR expression cell proliferation and tumor growth relative to control (MDA PCa 2b-Sham) cells. Interestingly, both TRAMP-C1-βarr1-GFP and MDA PCa 2b-βarr1 -/- xenografts showed a decrease in AKT phosphorylation, but an increase MAPK activation. Altogether, the data indicate that the effect of βarr1 in modulating AR signaling to regulate prostate cancer aggressiveness is cell and host autonomous.

ARRB1 reverses 5-FU-induced chemotherapeutic intestinal mucosal injury by protecting intestinal barrier and stem cell function

“…ARRB1 is a regulator of G protein-coupled receptors and a scaffold for linkage signaling networks. ARRB1 promotes tumor growth, cell proliferation, and apoptosis and has differential expression in a range of tumor tissues, including acute myeloid leukemia, hepatocellular liver carcinoma, and prostate cancer [10] .…”

“…ARRB1 can be regulated in the cytoplasm by a variety of non-GPCR pathways, including NF-KB and MAPK [6,7] , in addition to traditional GPCR desensitization and internalization. Furthermore, ARRB1 is linked to in ammatory reactions, carcinogenesis, and cell proliferation [7][8][9][10] .…”