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Metformin Has an Anti-Cancer Effect by Repressing TWIST/N-Cadherin Signaling
Rongbin Ge, MD, Ph.D, Zongwei Wang, Ph.D, Aria F. Olumi, MD.
MGH, Boston, MA, USA.

Background:
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/NF-kB 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. The anti-cancer effect of Metformin in vivo was analyzed by prostate cancer xenografts in athymic nude mice.
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. PC3 prostate cancer cells with stable over-expression of N-cadherin became resistant to metformin-mediated inhibition. Metformin-resistant PC3 cells were sub-cultured after long term exposure of cells to metformin. The metformin-resistant PC3 cells had higher baseline N-cadherin levels than the parental cells, and in contrast to the effect in the parental population, N-cadherin levels were not altered in the resistant population with metformin treatment. The expression of NF-kB and AP-1, the downstream molecules of N-cadherin, closely correlated with expression of N-cadherin after treatment with metformin. Silencing of N-cadherin with siRNA concurrently inhibited NF-kB p65. 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. Moreover, we evaluated the anti-cancer effect of metformin on prostate cancer xenografts and found metformin-treated mice had smaller tumors than vehicle-treated mice and tumor volume after metformin treatment is comparable to doxorubicin treatment.
Conclusions:
We demonstrate that metformin’s anti-cancer therapeutic effect may be mediated through repression of the TWIST/N-cadherin/NF-kB signaling pathway.


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