| First Author | Adekoya TO | Year | 2021 |
| Journal | Carcinogenesis | Volume | 42 |
| Issue | 5 | Pages | 772-783 |
| PubMed ID | 33710266 | Mgi Jnum | J:306507 |
| Mgi Id | MGI:6715685 | Doi | 10.1093/carcin/bgab021 |
| Citation | Adekoya TO, et al. (2021) Host versus cell-dependent effects of beta-arrestin 1 expression in prostate tumorigenesis. Carcinogenesis 42(5):772-783 |
| abstractText | 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 (betaarr1 and betaarr2), which are known to mediate G protein-coupled receptor desensitization and internalization, were also shown to modulate prostate tumorigenesis. betaarr1 is significantly overexpressed (>4-fold) in PCa cells relative to betaarr2. In this study, we investigated the effect of betaarr1 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 betaarr1 in TRAMP mice (TRAMP/betaarr1-/-) increased PCa growth and decreased overall survival relative to control TRAMP or TRAMP/betaarr2-/- animals. Prostate tissues from TRAMP/betaarr1-/- tumors displayed an increase in androgen receptor (AR) expression, whereas overexpression of betaarr1 in TRAMP-C1 (TRAMP-C1-betaarr1-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 betaarr1 expression in human MDA PCa 2b cells (MDA PCa 2b-betaarr1-/-) also decreased AR expression cell proliferation and tumor growth relative to control (MDA PCa 2b-Sham) cells. Interestingly, both TRAMP-C1-betaarr1-GFP and MDA PCa 2b-betaarr1-/- xenografts showed a decrease in AKT phosphorylation but an increase in MAPK activation. Altogether, the data indicate that the effect of betaarr1 in modulating AR signaling to regulate PCa aggressiveness is cell and host autonomous. |
