Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells
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Rongbin Ge1,*, Zongwei Wang1,*, Shulin Wu2, Yangjia Zhuo2,3, Aleksandar G. Otsetov1, Chao Cai2,3, Weide Zhong2,3, Chin-Lee Wu2, Aria F. Olumi1
1Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
3Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
*These authors have contributed equally to this work
Aria F. Olumi, e-mail: Olumi.Aria@mgh.harvard.edu
Keywords: prostate cancer, metformin, TWIST, N-cadherin
Received: May 13, 2015 Accepted: August 13, 2015 Published: August 24, 2015
Metformin has emerged as a potential anticancer agent. Here, we demonstrate that metformin plays an anti-tumor role via repressing N-cadherin, independent of AMPK, in wild-type N-cadherin cancer cells. Ectopic-expression of N-cadherin develops metformin-resistant cancer cells, while suppression of N-cadherin sensitizes cancer to metformin. Manipulation of AMPK expression does not alter sensitivity of cancer to metformin. We show that NF-kappaB is a downstream molecule of N-cadherin and metformin regulates NF-kappaB signaling via suppressing N-cadherin. Moreover, we also suggest that TWIST1 is an upstream molecule of N-cadherin/NF-kappaB signaling and manipulation of TWIST1 expression changes the sensitivity of cancer cells to metformin. In contrast to the cells that express N-cadherin, in N-cadherin deficient cells, metformin plays an anti-tumor role via activation of AMPK. Ectopic expression of N-cadherin makes cancer more resistant to metformin. Therefore, we suggest that metformin’s anti-cancer therapeutic effect is mediated through different molecular mechanism in wild-type vs. deficient N-cadherin cancer cells. At last, we selected 49 out of 984 patients’ samples with prostatic cancer after radical prostatectomy (selection criteria: Gleason score ≥ 7 and all patients taking metformin) and showed levels of N-cadherin, p65 and AMPK could predict post-surgical recurrence in prostate cancer after treatment of metformin.
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