Abstract 1093: Resveratrol inhibits prostate cancer metastasis by targeting microRNA-21

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: Most prostate cancer-related deaths are due to the metastatic form of the disease. Despite multimodal therapy, no effective treatment exists for metastatic prostate cancer. Resveratrol, a phytoalexin, has been reported to possess anticancer properties against various cancers. However, the exact mechanism underlying this beneficial effect is not clearly known. MicroRNA (miR)-21, an oncomir, is found to be up-regulated in prostate cancer and its levels are positively linked to cancer cell invasion and metastasis. In this study, we propose that resveratrol inhibition of miR-21 could account, in part, for its reduction in invasiveness and metastasis of prostate cancer cells. Methods: PC3-MM cells were treated with resveratrol and the levels of miR-21 and its target proteins, programmed cell death 4 (PDCD4) and maspin, were assessed by TaqMan assay and Western blotting, respectively. Cell viability was assessed by MTS assay, while invasion and migration were assessed by Boyden chamber assay and wound healing assay, respectively. Annexin-FITC and PI staining were performed to assess cell apoptosis. Microarray analyses were performed to identify different miRs which are regulated by resveratrol. Transient transfection of pre-miR-21 or PDCD4 siRNA was performed to elucidate the molecular mechanisms of resveratrol's antitumor action. Severe combined immunodeficient (SCID) mice were utilized to study the effect of oral administration of resveratrol on tumor growth and lung metastasis using subcutaneous and intravenous injections of PC3-MM cells. Results: Resveratrol significantly reduced PC3-MM cell viability and inhibited its invasion and migration in a dose-dependent manner. These anti-tumor effects of resveratrol were due to inhibition of miR-21 and increased expression of PDCD4, because transfection of PC3-MM cells with pre-miR-21 and PDCD4 siRNA reversed the anti-tumor effects of resveratrol. Resveratrol also decreased both serum and insulin growth factor 1 (IGF1)-activated Akt1 (p-Akt), a known regulator of miR-21. Inhibition of PI3 kinase by LY294002 mimicked resveratrol's response on cell viability and invasiveness. Furthermore, studies in SCID mice demonstrated that oral administration of resveratrol reduced PC3-MM tumor growth by inhibiting miR-21 and p-Akt and also reduced the ability of these cells to metastasize to the lung. Conclusion: We conclude that resveratrol inhibits PC3-MM prostate cancer cell viability, invasion and migration by suppressing miR-21 expression via a growth factor/Akt sensitive pathway. We propose that oral administration of resveratrol inhibits prostate cancer growth and metastasis by abrogating a growth factor/Akt signaling pathway for induction of miR-21. These data support the use of resveratrol as a miR-21 inhibitor for the treatment of metastatic prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1093. doi:1538-7445.AM2012-1093