Abstract 4974: Metformin has an anti-cancer effect by repressing TWIST/N-cadherin signaling

Abstract

Introduction and Objective Metformin, one of the most commonly used medications for treatment of type 2 diabetes, has emerged as a potential anticancer agent. The molecular mechanisms associated with the anti-cancer effect of metformin are poorly understood. We demonstrate, for the first time, that metformin inhibits prostate cancer proliferation through suppression of TWIST/N-cadherin signaling pathway. Methods RTαPCR, Western blot, immunofluorescence assays and confocal microscopy were applied to evaluate protein expression level. MTS assay and FACS analysis were applied to determine cellular proliferation. N-cadherin expression vectors were transfected into PC3 prostate cancer cells to establish stable cells with over-expression of N-cadherin. Metformin-resistant prostate cancer cells were established by exposure to higher concentrations (10mM) of metformin over 4 weeks. Results Treatment with metformin (5mM) inhibited proliferation in three different types of cancer cells (PC3-prostate cancer cells; T24-bladder cancer cells and 786-O- kidney cancer cells). Metformin treatment suppressed expression of N-cadherin in all cell types. Similar findings were observed by confocal microscopy. Expression of E-cadherin was not affected by metformin. Metformin-mediated repression of N-cadherin was dose and time- dependent in prostate cancer cells. PC3 prostate cancer cells with stable over-expression of N-cadherin became resistant to metformin-mediated inhibition. Stable PC3 prostate cancer cells after selection for metformin became resistant to metformin-mediated inhibition, and the metformin-resistant cancer cells had slightly higher baseline level of N-cadherin. In addition, in the metformin-resistant cells, N-cadherin levels were unchanged after treatment with metformin. The expression of AKT and AP-1, the downstream molecules of N-cadherin, closely correlated with expression of N-cadherin after treatment with metformin. Moreover, we also found that metformin inhibited expression of TWIST-1, a transcriptional activator of N-cadherin. Similar findings were observed by confocal microscopy. Conclusions We demonstrate that Metformin's anti-cancer therapeutic effect may be mediated through repression of the TWIST/N-cadherin signaling pathway.

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 4974. doi:1538-7445.AM2012-4974