自噬
PI3K/AKT/mTOR通路
细胞凋亡
蛋白激酶B
安普克
癌症研究
化学
卵巢癌
细胞生长
细胞生物学
程序性细胞死亡
活力测定
癌细胞
生物
癌症
生物化学
磷酸化
蛋白激酶A
遗传学
作者
Xinli Fan,Min Xie,Feijie Zhao,Jiajia Li,Chang-qing Fan,Hao Zheng,Zhentong Wei,Xinxin Ci,Songling Zhang
出处
期刊:Phytomedicine
[Elsevier]
日期:2021-02-01
卷期号:82: 153465-153465
被引量:26
标识
DOI:10.1016/j.phymed.2021.153465
摘要
Ovarian 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. In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Daph in ovarian cancer cells. The 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. We 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. Our 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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