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Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells.
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 30Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 6, no 30
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URN: urn:nbn:se:umu:diva-128209DOI: 10.18632/oncotarget.5023PubMedID: 26359363OAI: oai:DiVA.org:umu-128209DiVA, id: diva2:1050545
Available from: 2016-11-29 Created: 2016-11-29 Last updated: 2018-06-09

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Otsetov, Aleksandar G

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