Daphnetin triggers ROS-induced cell death and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway in ovarian cancer |
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| Affiliation: | 1. Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China;2. Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China;1. Department of Nephrology, Henan Provincial People''s Hospital, People''s Hospital of Zhengzhou University, No.7, Weiwu Road, Jinshui, Zhengzhou 450003, China;2. Department of Ophthalmology, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, 450000, China;1. Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates;2. College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;3. College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511 Egypt |
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| Abstract: | BackgroundOvarian cancer is one of the most common gynecological malignancies in the world. Daphnetin (Daph) was previously reported to possess antitumor potential, but its potential and molecular mechanisms in ovarian cancer remain poorly understood.PurposeIn the current study, we aimed to explore the antitumor effect and detailed mechanisms of Daph in ovarian cancer cells.MethodsThe cytotoxic effect of Daph on ovarian cells was determined in vitro and in vivo. Cell growth, proliferation, apoptosis and ROS generation were measured by CCK8 assays, colony formation assays and flow cytometry. Western blotting was used to evaluate the related signal proteins. Immunofluorescence and transmission electron microscopy were used to evaluate markers of autophagy and autophagic flux. The antitumor effects were observed in the A2780 xenograft model. Moreover, Daph-induced autophagy was observed by enhanced LC3-II accumulation and endogenous LC3 puncta, and an autophagy inhibitor further enhanced the antitumor efficacy of Daph, which indicated that the cytoprotective role of autophagy in ovarian cancer.ResultsWe found that Daph exhibited antitumor effects by inducing ROS-dependent apoptosis in ovarian cancer, which could be reversed by N-acetyl cysteine (NAC). The AMPK/Akt/mTOR pathway was involved in Daph-mediated cytoprotective autophagy, and when Daph-mediated the expression level of AMPK and autophagy were blocked, there was robust inhibition of cell proliferation and induction of apoptosis. In addition, in the A2780 xenograft model, combined treatment with Daph and an autophagy inhibitor showed obvious synergetic effects on the inhibition of cell viability and promotion of apoptosis, without any side effects.ConclusionOur results suggest that Daph triggers ROS-induced cell apoptosis and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway. Moreover, the combination of Daph and autophagy inhibitor may be a potential therapeutic strategy for ovarian cancer. |
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