Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition <i>via</i> βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Liu, Zhao; Qi, Shasha; Zhao, Xianxian; Li, Mingjiang; Ding, Sentai; Lü, Jiaju; Zhang, Hui

doi:10.18632/oncotarget.7040

Cited by 44 publications

(54 citation statements)

References 51 publications

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“…Our study findings with metformin and compound C, not only support for the anti‐fibrotic effects of metformin, but also indicate that metformin's effects on albumin‐induced EMT are independent to that of AMPK activation in renal cells. This was evident from metformin's persistent inhibitory effect on α‐SMA expression despite AMPK inhibition using compound C. Consensus with our findings, a study by Liu, Qi, et al (2016) in endometrial carcinoma (KLE cells) reported that the addition of compound C did not alter metformin's ability to prevent EMT associated with cancer progression (Liu, Qi, et al, ). Thus, we infer that metformin's inhibitory effects on EMT are AMPK‐independent.…”

Section: Discussionsupporting

confidence: 90%

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

Allouch

Munusamy

2017

Journal Cellular Physiology

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Proteinuria (albuminuria) plays a crucial role in the etiology of chronic kidney disease (CKD) via alteration of multiple signaling pathways and cellular process in renal cells. The objectives of this study are to investigate the effects of activation of the energy-sensing molecule AMP-activated kinase (AMPK) in renal cells using metformin on endoplasmic reticulum (ER) stress, AKT, mTOR, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis that are thought to mediate renal cell injury during proteinuria, and to dissect the AMPK- and non-AMPK mediated effects of metformin using an in vitro model of albumin-induced renal cell injury. Rat renal proximal tubular (NRK-52E) cells were exposed to 10 and 15 mg/ml of albumin for 72 h in the presence of 1 mM Metformin and/or 0.5 µM compound C, and assessed for alterations in the aforementioned pathways. Metformin treatment restored AMPK phosphorylation and augmented autophagy in renal cells exposed to albumin. In addition, metformin treatment attenuated the albumin-induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin-mediated inductions of EMT marker (α-SMA), pro-apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells. Blockade of metformin-induced AMPK activation with compound C blunted the ER defense response and autophagy but had no effect on the markers of EMT and apoptosis in our model. Our studies suggest that metformin protects renal cells against proteinuric cytotoxicity via suppression of AKT and mTOR activation, inhibition of EMT and apoptosis, and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms, respectively.

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Section: Discussionsupporting

confidence: 90%

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

Allouch

Munusamy

2017

Journal Cellular Physiology

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“…Moreover, the potential role of metformin in treating gynecologic oncology has been explored in a number of studies. A study reported that metformin inhibits βKlotho-related ERK1/2 signaling and AMPKα signaling to reverse the EMT in endometrial adenocarcinoma [26]. However, none of research involves the relationship of mTOR pathway and PKM2.…”

Section: Introductionmentioning

confidence: 99%

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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“…The plausible mechanism underlying this synergistic anti-proliferative effect of the metformin and MPA combination on Ishikawa cells could include AMPK-independent pathways, including factors of the Rag family of GTPases, hypoxia inducible factor (HIF) target gene, and regulated in development and the DNA damage response I (REDD1) (17). Other studies confirmed that there was no significant increase in p-AMPKα expression at low doses of metformin, ≤ 1000 μM, in Ishikawa, KLE, and USPC cells (18, 19). In these studies, high dose metformin ≥10 mM was shown to be necessary to bring about a significant increase in p-AMPKα expression.…”

Section: Discussionmentioning

confidence: 84%

“…However, our study has some limitations in that metformin was not shown as an AMPK activator. However, there are a few studies which did not support metformin as a potent AMPK activator, not only in proliferation (18), but also in invasion (22). Some values were out of the expected ranges, for example, MMP-9 concentration after treatment with 1000 μM metformin only, which was expected to be lower than that of 100 μM metformin.…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Suh

Lee

Park

et al. 2019

Preprint

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18This study was performed to evaluate the anticancer effects of tolerable doses of metformin 19 with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell 20 invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-21 β1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, 22 and USPC) after treatment with different dose combinations of MPA (0, 10 µM) and metformin 23 (0, 100, 1000 µM). Combining metformin (0, 100, 1000 µM) and 10 µM MPA induced 24 significantly decreased cell viability in a time-and dose-dependent manner in Ishikawa cells, 25 but not in KLE and USPC cells. There was no dose-or time-dependent cell growth inhibition, 26 or positive western blot results for the expression of progesterone receptors and phospho-27 AMPKα, following treatment with any combination of metformin (0, 100, 1000 µM) and 10 28 µM MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly 29 inhibited cell invasion in a dose-dependent manner (1.31±0.05, 0.94±0.04, 0.83±0.05 at 0, 100 30 µM, 1000 µM, respectively; p<0.0005). The inhibitory effect of metformin was reversed to 31 create a stimulating effect when metformin was combined with 10 µM MPA (1.10±0.05, 32 1.42±0.18, 1.41±0.26 at 0, 100, 1000 µM, respectively; p<0.005). MMP-9 and TGF-β1 showed 33 similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of 34 metformin in KLE cells was completely reversed to the state of no treatment by the addition of 35 MPA; this might be mediated through MMP-9 and TGF-β1. Our study suggests the possibility 36 of these combinations doing harm, rather than good, under some conditions. 3 37Recently, metformin, an oral biguanide anti-diabetic drug for type 2 diabetes, was 55 shown to have significant anticancer activity and considered a novel treatment option through 56 drug repositioning (4), including for endometrial cancer (5-7). However, it should be noted that 57 almost all previous studies were conducted with supra-pharmacological concentrations (doses) 58 of metformin, that is, 10-100 times higher than maximally achievable therapeutic 59 concentrations found in patients with type 2 diabetes mellitus (8). Such levels exceed the 4 60 maximum dose that could cause lactic acidosis, one of the most serious side effects of 61 metformin. Any anticancer effect of metformin should be studied only in the condition of 62 achievable therapeutic concentrations (8, 9). 63Another approach for the development of novel anticancer drug regimens is the use of 64 drug combinations. Although hormonal therapy is currently recommended only for lower-65 grade endometrioid histology in clinical guidelines, there is evidence suggesting several 66 anticancer mechanisms of progestational agents, which could show significant effects in 67 poorly-differentiated endometrioid adenocarcinoma, as well as USPC (2, 10, 11), particularly 68 when combined with metformin (12). 69The purpose of this study w...

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Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Cited by 44 publications

References 51 publications

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

Metformin attenuates albumin‐induced alterations in renal tubular cells in vitro

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

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

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