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Oncotarget. 2015 Oct 6;6(30):28973-87. doi: 10.18632/oncotarget.5023.

Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells.

Author information

1
Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.

Abstract

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.

KEYWORDS:

N-cadherin; TWIST; metformin; prostate cancer

PMID:
26359363
PMCID:
PMC4745705
DOI:
10.18632/oncotarget.5023
[Indexed for MEDLINE]
Free PMC Article

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