Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells

Likun Gao,Zhi Wang,Jinling Huang,Jin Liu,Li Hong,Danhua Lu

doi:10.1038/s41419-019-1849-x

Abstract

Paeonol (Pae), a phenolic acid compound isolated from the Moutan Cortex, was previously demonstrated to exert multiple anticancer effects. The rational control of autophagy has been considered a potential treatment strategy for epithelial ovarian cancer. However, whether Pae induces autophagy and the relationship between its antitumour activities and autophagy in epithelial ovarian cancer are still unclear. In this study, we found that Pae induced not only antiproliferation activity and apoptosis but also autophagy, and complete autophagic flux was observed in A2780 and SKOV3 cells. In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin. These results indicate that autophagy induced by Pae has a cytoprotective role in both A2780 and SKOV3 cells. Mechanistically, we found that Pae inhibited the protein kinase B(Akt)/mammalian target of rapamycin (mTOR) pathway. Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer.

Highlights

Epithelial ovarian cancer (EOC) continues to be the most frequent gynaecologic malignancy, and it ranks as the fifth leading cause of cancer-related mortality among women worldwide[1]
Consistent with our previous data[12], an increase in both early and late apoptosis in A2780 and SKOV3 cells was induced in a dose-dependent manner after Pae treatment, and the results showed that there were slightly less apoptotic cells observed in Pae-treated ovarian cancer cells when compared to cisplatin-treated (IC50 value was about 10 μM) positive control cells (Fig. 2a)
To ascertain whether the Akt/mammalian target of rapamycin (mTOR) pathway has an important role in Pae-induced autophagy, we investigated key proteins related to the Akt/mTOR pathway in Pae-treated ovarian cancer cells by western blot analysis

Summary

Introduction

Epithelial ovarian cancer (EOC) continues to be the most frequent gynaecologic malignancy, and it ranks as the fifth leading cause of cancer-related mortality among women worldwide[1]. Acquired chemoresistance remains a major obstacle for the cure of EOC, and novel effective treatments are still urgently needed. Paeonol (Pae; 2′-hydroxy-4′-methoxyacetophenone), a phenolic acid compound derived from the root bark of the Moutan Cortex (Paeonia suffruticosa)[7], has been reported to possess all types of potent properties, including antiinflammatory[8], antioxidant[9], immune regulatory activity[10], and reverse chemoresistance[11]. Pae was shown to exhibit favourable anticancer activities in ovarian cancer cells[12,13] and other types of cancer cell lines, such as prostate cancer[14], melanoma[15], lung cancer[16], gastric cancer[17], and colon cancer[18]. The antitumour activity of Pae has been suggested by cumulative evidence, the detailed

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Conclusion