You have accessJournal of UrologyProstate Cancer: Basic Research (IV)1 Apr 2013803 METFORMIN HAS AN ANTI-CANCER EFFECT BY REPRESSING TWIST/N-CADHERIN SIGNALING Rongbin Ge, Zongwei Wang, and Aria Olumi Rongbin GeRongbin Ge Boston, MA More articles by this author , Zongwei WangZongwei Wang Boston, MA More articles by this author , and Aria OlumiAria Olumi Boston, MA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.367AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 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 RT–PCR, 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 and TWIST-1 expression vectors were transfected into PC3 prostate cancer cells to establish stable cells with over-expression of N-cadherin and TWIST-1, respectively. 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. In contrast to N-cadherin, 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. PC3 prostate cancer cells with stable over-expression of TWIST-1 became resistant to metformin-mediated inhibition. CONCLUSIONS We demonstrate that Metformin's anti-cancer therapeutic effect may be mediated through repression of the TWIST/N-cadherin signaling pathway. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e330-e331 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rongbin Ge Boston, MA More articles by this author Zongwei Wang Boston, MA More articles by this author Aria Olumi Boston, MA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...