The Roles of Autophagy, Ferroptosis and Pyroptosis in the Anti-ovarian Cancer Mechanism of Harmine and Their Crosstalk

Overview

Journal Sci Rep

Specialty Science

Date 2024 Mar 19

PMID 38499622

Authors

Jun Zhu

Hong Zhu

Qing Zhu

Shi Lei Xu

Lu Xiao

Ming Yue Zhang

Jun Gao

Affiliations

Soon will be listed here.

Abstract

This study aimed to investigate the role of autophagy, ferroptosis, and pyroptosis in the antitumour mechanism of harmine (Har) and its crosstalk in ovarian cancer. By transmission electron microscopy, we found that compared with those in the control group, the cytoplasm of human ovarian cancer cells (SKOV3) treated with Har showed increased numbers of autophagic vesicles, decreased intracellular mitochondrial volume, increased bilayer membrane density, and decreased cristae. Western blot, immunofluorescence, and monodasylcadaverine (MDC) staining all suggested that Har promoted autophagy in SKOV3 cells. LY294002 and siFOXO3 rescued the inhibition of the PI3K/AKT/mTOR/FOXO3 signalling pathway and the promotion of autophagy by Har. Additionally, the levels of ferroptosis- and pyroptosis-related proteins and the levels of Fe , glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) suggested that Har promoted ferroptosis and pyroptosis in SKOV3 cells. Interestingly, pretreatment with chloroquine (CQ), erastin, rapamycin (Rap), or ferrostatin-1 (Fer-1) increased or reversed the ferroptosis and pyroptosis promoted by Har, respectively. In vivo, the volume of tumours in the Har group was decreased, and immunohistochemistry revealed decreased levels of Ki-67 and GPX4 and increased levels of ATG5 and NARL3. In conclusion, Har exerts its anti-ovarian cancer effect not only by promoting autophagy by regulating the PI3K/AKT/mTOR/FOXO3 signalling pathway but also by promoting ferroptosis and pyroptosis. Additionally, there is complex crosstalk between autophagy, ferroptosis, and pyroptosis in ovarian cancer.

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