Daphnetin triggers ROS-induced cell death and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR
Xiaoye Fan1, Min Xie2, Feijie Zhao2
1Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China; Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
Background:
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.
Purpose:
In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Daph in ovarian cancer cells.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Daphnetin (Daph) shows antitumor effects in ovarian cancer by inducing reactive oxygen species (ROS)-dependent apoptosis. It also triggers protective autophagy via the AMPK/Akt/mTOR pathway, suggesting a potential therapeutic strategy when combined with autophagy inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian cancer is a leading gynecological malignancy globally.
- Daphnetin (Daph) shows potential antitumor activity, but its mechanisms in ovarian cancer are unclear.
Purpose of the Study:
- To investigate the antitumor effects of Daph in ovarian cancer cells.
- To elucidate the molecular mechanisms underlying Daph's action in ovarian cancer.
Main Methods:
- In vitro and in vivo studies assessed Daph's cytotoxic effects, cell proliferation, apoptosis, and ROS generation.
- Western blotting, immunofluorescence, and transmission electron microscopy analyzed signaling pathways and autophagy.
- An A2780 xenograft model evaluated in vivo efficacy and combined treatment effects.
Main Results:
- Daph induced reactive oxygen species (ROS)-dependent apoptosis in ovarian cancer cells, reversible by N-acetyl cysteine (NAC).
- Daph-mediated cytoprotective autophagy involved the AMPK/Akt/mTOR pathway; blocking this pathway enhanced apoptosis and inhibited proliferation.
- Combined Daph and autophagy inhibitor treatment showed synergistic antitumor effects in a xenograft model with no observed side effects.
Conclusions:
- Daphnetin triggers ROS-induced apoptosis and activates cytoprotective autophagy through the AMPK/Akt/mTOR pathway in ovarian cancer.
- Combining Daphnetin with an autophagy inhibitor presents a promising therapeutic strategy for ovarian cancer treatment.
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