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Metformin Mechanism of Inhibiting PI3K/mTOR through CCNB1 and Affecting Epithelial-Mesenchymal Transition in Ovarian Cancer Cells
Vol 38, Issue 3, 2024
Abstract
Background: Ovarian cancer (OC), the third most common gynecological tumor, has a high mortality rate. Epidemiological data suggest that metformin may be useful for treating OC patients, however, the relevant mechanisms remain unclear. This study aimed to decipher the mechanism of metformin in the treatment of OC. Methods: The OC cell lines A2780 and SKOV3 were subjected to metformin treatment (10 mM) alone or in combination with an mammalian target of rapamycin (mTOR) agonist (2 nM MHY1485), concurrently suppressing Cyclin B1 (CCNB1) expression. Then, Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell, and wound healing assays were performed to observe cell proliferation, migration, invasion, and apoptosis, respectively. In addition, Western blot and quantitative reverse transcription PCR (qRT-PCR) were used to test the expression of CCNB1, phosphatidylinositol-3-kinase (PI3K)/mTOR signaling pathway-related proteins, and epithelial-mesenchymal transition (EMT)-associated molecules (Vimentin, E-Cadherin). Results: Metformin significantly inhibited the OC cells proliferation, migration and invasion, while inducing apoptosis. Meanwhile, metformin significantly inhibited CCNB1 expression. Reducing CCNB1 expression enhanced the inhibitory effect of metformin on OC cells. Additionally, metformin inhibited the PI3K/mTOR signaling pathway proteins and Vimentin expression, while upregulating E-Cadherin expression. However, mTOR agonist partially reversed the effect of metformin on OC cells. Conclusions: Metformin reduced CCNB1 expression, inhibited EMT and the PI3K/mTOR signaling pathway, which in turn inhibited OC cell function.
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Copyright (c) 2024 Jing-fang Wang, Wen-hao Wang, Fang Wei, Wei-hong Zhao, Ke-yan Cheng, Li-li Zhang, Xin Bai, Rui Zhang, Wei-min Kong
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy