Metformin is a novel suppressor for transforming growth factor (TGF)-β1

Xiao, Han; Zhang, Jianshu; Xu, Zhonghe; Feng, Yenan; Zhang, Mingliang; Liu, Jianli; Ruifei, Chen; Shen, Jing; Wu, Jimin; Lu, Zengjun; Fang, Xiaohong; Li, Jingyuan; Zhang, Youyi

doi:10.1038/srep28597

Cited by 79 publications

(76 citation statements)

References 26 publications

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“…There are two possibilities for the AMPKα2‐independent effects, AMPK‐independent effects and AMPKα1‐dependent effects. Indeed, several other studies have reported that metformin acts via AMPK‐independent pathways . In our previous study, which used Compound C (an AMPK inhibitor) and a dominant‐negative adenovirus to inhibit AMPK activity, we found that metformin nonetheless inhibits TGFβ1‐induced collagen synthesis in cardiac fibroblasts .…”

Section: Discussionmentioning

confidence: 65%

Metformin attenuates renal fibrosis in both AMPKα2‐dependent and independent manners

Feng

Wang

Zhang

et al. 2017

Clin Exp Pharma Physio

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Metformin is a well-known AMP-activated protein kinase (AMPK) activator, and it has been shown to inhibit organ fibrosis. Whether AMPKα2 mediates metformin protection against renal fibrosis remains unknown. Here, we aimed to investigate the role of the AMPKα2 isoform in mediating the inhibitory effect of metformin on renal fibrosis. Unilateral ureteral obstruction (UUO) was used to induce renal fibrosis in wild-type (WT) and AMPKα2 knockout (AMPKα2 ) mice. Metformin treatment was initiated 3 days before UUO and was continued until 7 days after UUO. In WT mice, metformin significantly inhibited UUO-induced renal fibrosis. In AMPKα2 mice, metformin also tended to inhibit UUO-induced renal fibrosis. Specifically, metformin significantly reduced UUO-induced transforming growth factor β1 (TGFβ1) mRNA and protein expression in WT mice but not in AMPKα2 mice. In contrast, metformin reduced UUO-induced TGFβ1 downstream Smad3 phosphorylation in both WT and AMPKα2 mice, suggesting that this regulation occurs in an AMPKα2-independent manner. In conclusion, the underlying mechanisms for the protective effects of metformin against renal fibrosis include AMPKα2-dependent targeting of TGFβ1 production and AMPKα2-independent targeting of TGFβ1 downstream signalling. In this regard, metformin has an advantage over other AMPK activators for the treatment of renal fibrosis.

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Section: Discussionmentioning

confidence: 65%

Metformin attenuates renal fibrosis in both AMPKα2‐dependent and independent manners

Feng

Wang

Zhang

et al. 2017

Clin Exp Pharma Physio

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“…Recent studies indicated that metformin was a novel TGF-β suppressor with therapeutic potential for numerous diseases [33]. In our study, we used TGF-β1 to induce EMT and explore the possible mechanism of metformin that inhibited TGF-β1-induced EMT in cervical cancer.…”

Section: Discussionmentioning

confidence: 98%

Metformin Inhibits TGF-β1-Induced Epithelial-to-Mesenchymal Transition via PKM2 Relative-mTOR/p70s6k Signaling Pathway in Cervical Carcinoma Cells

Cheng

Hao

2016

IJMS

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Background: Epithelial-to-mesenchymal transition (EMT) plays a prominent role in tumorigenesis. Metformin exerts antitumorigenic effects in various cancers. This study investigated the mechanisms of metformin in TGF-β1-induced Epithelial-to-mesenchymal transition (EMT) in cervical carcinoma cells. Methods: cells were cultured with 10 ng/mL TGF-β1 to induce EMT and treated with or without metformin. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis were analyzed by flow cytometry; cell migration was evaluated by wound-healing assay. Western blotting was performed to detect E-cadherin, vimentin, signal transducer and activator of transcription 3 (STAT3), snail family transcriptional repressor 2 (SNAIL2), phosphorylation of p70s6k (p-p70s6k) and -Pyruvate kinase M2 (PKM2) Results: TGF-β1 promoted proliferation and migration, and it attenuated apoptosis compared with cells treated with metformin with or without TGF-β1 in cervical carcinoma cells. Moreover, metformin partially abolished TGF-β1-induced EMT cell proliferation and reversed TGF-β1-induced EMT. In addition, the anti-EMT effects of metformin could be partially in accord with rapamycin, a specific mTOR inhibitor. Metformin decreased the p-p70s6k expression and the blockade of mTOR/p70s6k signaling decreased PKM2 expression. Conclusion: Metformin abolishes TGF-β1-induced EMT in cervical carcinoma cells by inhibiting mTOR/p70s6k signaling to down-regulate PKM2 expression. Our study provides a novel mechanistic insight into the anti-tumor effects of metformin.

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“…Metformin was also identified as a novel TGFβ1 suppressor [16]. VEGF has been shown to play a vital role in the regulation of physiological and pathological angiogenesis [17].…”

Section: Western Blot Represents One Of Three Independent Experimentsmentioning

confidence: 99%

WITHDRAWN: Metformin antagonizes MPS-1-mediated IL-6/Stat3 signaling in ovarian cancer cells: possible mechanisms of stemness and angiogenesis inhibition

Xu¹,

Ding²,

Yang³

2018

Oncotarget

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To unveil the potential antitumor effects of metformin against ovarian cancer cells and the underlying molecular mechanisms involved, SKOV3 ovarian cancer cells were exposed to the indicated concentrations of metformin (0, 2, 4, 8 and 16 μM). The effects of metformin on SKOV3 cells were monitored using CCK-8 assay for cell viability, colony formation assay for cell growth, scratch assay for cell migration, TUNEL assay and flow cytometry analysis for apoptosis. In the present study, metformin treatment dose-dependently inhibited cell growth with IC 50 values of 16 μM, induced cell apoptosis and decreased the capacity of cell migration. The stemness of SKOV3 cells was impaired, as indicated by significant decrease in stem cell markers SOX2 and OCT4 expressions. Increased capillary-like structure formation and downregulated VEGF and TGFβ1 expressions were observed in response to metformin treatment. Furthermore, western blot showed that 16 μM metformin significantly decreased MPS-1 protein followed by the downregulation of IL-6 protein expression and phosphorylation of Stat3. Collectively, these data indicate that metformin exerts anticancer effects by suppressing stemness and angiogenesis, which at least in part attributes to MPS-1-mediated IL-6/p-Stat3 signaling.

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Metformin is a novel suppressor for transforming growth factor (TGF)-β1

Cited by 79 publications

References 26 publications

Metformin attenuates renal fibrosis in both AMPKα2‐dependent and independent manners

Metformin attenuates renal fibrosis in both AMPKα2‐dependent and independent manners

Metformin Inhibits TGF-β1-Induced Epithelial-to-Mesenchymal Transition via PKM2 Relative-mTOR/p70s6k Signaling Pathway in Cervical Carcinoma Cells

WITHDRAWN: Metformin antagonizes MPS-1-mediated IL-6/Stat3 signaling in ovarian cancer cells: possible mechanisms of stemness and angiogenesis inhibition

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