Alantolactone triggers oxeiptosis in human ovarian cancer cells via Nrf2 signaling pathway

• Published in: Biochemistry and biophysics reports 2023-09, Vol.35, p.101537, Article 101537
• Main Authors: Nasirzadeh, Mahdieh, Atari Hajipirloo, Somayeh, Gholizadeh-Ghaleh Aziz, Shiva, Rasmi, Yousef, Babaei, Ghader, Alipour, Shahriar
• Format: Article
• Language: English
• Subjects: Alantolactone; Nrf2 signaling pathway; Ovarian cancer; Oxeiptosis
• ISSN: 2405-5808; 2405-5808
• DOI: 10.1016/j.bbrep.2023.101537

A growing body of evidence indicated that Alantolactone (ALT) promotes Reactive Oxygen Species (ROS) generation exclusively in cancer cells. Therefore, the aim of this study was to investigate the effect of ALT on the molecular mechanism of oxeiptosis, as a novel cell death pathway due to the high levels of intracellular ROS in ovarian cancer. MTT assay was used to evaluate the effect of ALT on SKOV3 cell viability. mRNA and protein expression levels of Nrf2 (nuclear factor erythroid 2–related factor 2), KEAP1 (Kelch-like ECH-associated protein 1), PGAM5 (phosphoglycerate mutase family member 5), AIFM1 (Mitochondrial Apoptosis-Inducing Factor), Glutathione synthetase (GSS) and glutathione peroxidase (GPX) were analyzed by real time PCR and western blotting methods respectively. Our findings showed that ALT inhibits the proliferation of skov3 cells in a time and dose dependent manner and IC50 was 32 μM at 24h. A significant down-regulation of Nrf2, GSH and GPX mRNA levels was seen in skov3 cells incubated with 32 and 64 μM of ALT in comparison with control group, while, mRNA expression levels of PGAM5 and KEAP1 were increased. Western blot analysis showed that ALT significantly decreases protein levels of Nrf2 and increases PGAM5 and KEAP1. ALT dephosphorylated PS116-AIFM1 and total AIFM1 protein level was elevated. Our results provided evidence that ALT could be a potential option for ovarian cancer treatment by ROS-mediated oxeiptosis. •ALT inhibits ovarian cancer cell proliferation.•ALT induce ROS overproduction by suppressing Nrf2.•ROS elevation was followed by PGAM5 upregulation.•PGAM5 dephosphorylate AIFM1 and induce oxeiptosis cell death pathway.