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Metformin represses...
Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells.
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Ge, Rongbin (author)
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Wang, Zongwei (author)
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Wu, Shulin (author)
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Zhuo, Yangjia (author)
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Otsetov, Aleksandar G (author)
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Cai, Chao (author)
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Zhong, Weide (author)
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Wu, Chin-Lee (author)
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Olumi, Aria F (author)
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- 2015-08-24
- 2015
- English.
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:30
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http://www.oncotarge...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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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