Abstract 1152: Micro RNA-21 serves as an essential target for resveratrol's anti-tumor action against metastatic prostate cancer cells

Abstract

Abstract Background: Resveratrol, a phytoalexin, has been reported to possess benefits against various cancers. However, the exact mechanism(s) underlying this beneficial response is not clearly understood. MicroRNA-21 (miR-21) is a small non-coding RNA which represses the translation of various tumor-suppressor genes. miR-21 levels are often upregulated in prostate cancer where it is positively associated with increased proliferation, invasion and metastasis and reduced apoptosis. Here, we demonstrate that resveratrol negatively regulates proliferation, invasion and apoptosis by modulating the levels of miR-21 in an androgen-independent, metastatic prostate cancer line (PC-3MM). Methods: The effect of resveratrol on PC-3MM cell proliferation at different time points was measured using MTS assay. Apoptosis and cell cycle analysis were determined by flow cytometry. The effects of resveratrol on invasion and migration were assessed by Boyden chamber and wound healing assays, respectively. miR-21 levels were determined by real-time PCR. Western blotting was used to assess modulation of miR-21 downstream proteins. In addition, siRNA transfections were performed to suppress the expression of specific proteins in order to elucidate the molecular mechanisms underlying the actions of resveratrol. Results: We observed that resveratrol significantly reduced proliferation of PC-3MM cells in a dose-dependent manner. This anti-proliferative effect of resveratrol was due to the induction of cell cycle arrest in G2/M and S phase and increased apoptosis at 25 and 50 μM doses of resveratrol. Resveratrol also inhibited cell invasion and migration in a dose-dependent manner in Boyden chamber and wound healing assays, respectively. These changes were associated with reduced miR-21 expression and increased expression of miR-21-tumor suppressor targets, such as maspin and program cell death 4 (PDCD4). Inhibition of miR-21 by mir21 antisense oligonucleotide also had the same effect on maspin and PDCD4 expression. Furthermore, resveratrol induced inhibition of proliferation, invasion and migration of PC-3MM cells were reversed by overexpressing pre-miR-21 or knockdown of PDCD4 by siRNA. Conclusion: This study demonstrates, for the first time, that resveratrol can inhibit miR-21 expression which could account for its anti-tumor effects, such as inhibition of proliferation, invasion and migration of PC-3MM prostate cancer cells. Inhibition of miR-21 occurs at doses of resveratrol (25 and 50 μM) which are readily achieved in vivo following consumption of resveratrol in red wine and grapes. Based up on these interesting results, we propose that resveratrol could serve as a potential dietary supplement for cancer chemoprevention or as an adjunct to existing chemotherapeutic regimens for treating prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2011-1152