Abstract 4384: Targeting miR-124 inhibits growth of prostate cancer xenografts and sensitized prostate cancer cells to anti-androgen

Abstract

Abstract Increasing evidence has shown that miR-124 is a tumor suppressor and plays an important role in pathogenesis of many types of human cancer. We previously found that miR-124 directly targets the androgen receptor (AR) and is significantly downregulated in clinical prostate cancer (CaP) samples. Moreover, overexpression of miR-124 induced apoptosis and inhibited cell proliferation and xenograft growth of CaP. In this study, we determined whether restoration of miR-124 may represent an adjunctively therapeutic option for CaP treatment. For this purpose, WST-1 and clonogenic assays were performed to evaluate the effects of miR-124 or miR-124 plus enzalutamide (one new androgen antagonist) on CaP cell proliferation. In animal experiment, male nude mice were inoculated s.c with CWR22 CaP cell suspensions. When tumor sizes reached ∼50 mm3, mice were treated with polyethylenimines (PEI)-complexed miR-124 (i.v., 10µg/day, thrice a week for 4 weeks) or PEI-miR-124 (i.v.) plus enzalutamide (p.o., 10mg/kg/day for 5 weeks). PEI can increase internalization and facilitate miRNA release into cytoplasm. After treatment, tumors were harvested for analyzing apoptosis and measuring miR-124 target levels. In in vitro experiment, 22Rv1 cells were separately treated with miR-124, enzalutamide or both. It was found that the combined treatment significantly increased growth inhibition of 22Rv1 cells. In addition, we established enzalutamide-resistant 22Rv1 subline (22Rv1-MDVR) by clone-selection in gradually increased doses (from 5μM to 40μM within four months). Treatment with miR-124 obviously inhibited clone formation of 22Rv1-MDVR cells. In mice receiving miR-124 or enzalutamide treatment, we observed tumor-inhibitory effects. However, the combination of miR-124 and enzalutamide exhibited more significant inhibition of tumor growth when compared to the single treatment. We examined the expression of AR and its variant 7 (AR-V7) that are targets of miR-124. Reduced levels of AR and AR-V7 were found in miR-124-treated tumors, indicating that PEI facilitates entry of miR-124 into the tumor cells. We also observed increased apoptosis in miR-124-treated tumors. Data from in vitro and in vivo studies show that miR-124 inhibited growth of CaP cells and sensitized CaP cells to anti-androgens, suggesting that miR-124 can be used as an adjunctively therapeutic agent for improved CaP treatment. Citation Format: Xu-Bao Shi, Aihong Ma, Lingru Xue, Ralph W. deVere White. Targeting miR-124 inhibits growth of prostate cancer xenografts and sensitized prostate cancer cells to anti-androgen. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2014-4384