Astragalus polysaccharides sensitize ovarian cancer stem cells to PARPi by inhibiting mitophagy via PINK1/Parkin signaling
Qiaohua Peng,
Yan Yu,
Lele Ye,
Songfa Zhang,
Yang Li,
Xiaoping Hua,
Shizhen Shen,
Dongxiao Hu,
Weiguo Lu
Affiliations
Qiaohua Peng
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Yan Yu
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Lele Ye
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Songfa Zhang
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Yang Li
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China; Zhejiang Key Laboratory of Maternal and Infant Safety, Women’s Hospital School of Medicine Zhejiang University, Hangzhou 310000, China
Xiaoping Hua
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Shizhen Shen
Zhejiang Key Laboratory of Maternal and Infant Safety, Women’s Hospital School of Medicine Zhejiang University, Hangzhou 310000, China
Dongxiao Hu
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
Weiguo Lu
Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China; Zhejiang Key Laboratory of Maternal and Infant Safety, Women’s Hospital School of Medicine Zhejiang University, Hangzhou 310000, China; Zhejiang Privincial Clinical Research Center for Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China; Corresponding author
Summary: Ovarian cancer (OC) remains the most lethal gynecological malignant tumor. PARP inhibitors (PARPi) have significantly improved survival, particularly in patients with OC with BRCA1/2 mutations. However, the majority of patients eventually develop resistance to PARPi. Cancer stem cells (CSCs) are considered the source of drug resistance in cancer. Our study found that the synergistic effect of astragalus polysaccharides (APSs) and PARPi was observed in ovarian cancer stem cells (OCSCs) by decreasing cell viability and self-renewal potential while inducing apoptosis. The present study also demonstrated that OCSCs had increased mitophagy. Furthermore, it was observed that APS in combination with PARPi inhibits mitophagy and downregulates the PINK1 protein level in OCSCs. The overexpression of PINK1 via the pEGFP(+)-PINK1 plasmid resulted in a partial reversal of the increased susceptibility of OCSCs when PARPi were administrated concurrently with APS. In conclusion, APS increases OCSC sensitivity to PARPi by inhibiting mitophagy via the PINK1/Parkin pathway regulation.
