Abstract 2320: Heme oxygenase-1 mediates ferroptosis

Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-κB-independent manner. This study was aimed to characterize the underlying mechanism by BAY and demonstrate its potential chemotherapeutic targets for cancer treatment. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death in human breast cancer cells (MDA-MB-231 and MDA-MB-468) and glioblastoma cells (DBTRG-05MG). The results from quantitative real-time PCR and western blotting analysis showed that BAY upregulated a variety of nuclear factor-E2-related factor 2 (Nrf2) target genes related to redox regulation, particularly heme oxygenase-1 (HO-1) and solute carrier family 7 membrane 1 (SLC7A11). Studies with pharmacological inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. Our study discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and provided new insights to understand the mechanism of HO-1-induced ferroptosis, suggesting HO-1 as a new chemotherapeutic target for cancer treatment. Citation Format: Shih-Kai Chiang, Shuen-Ei Chen, Ling-Chu Chang. Heme oxygenase-1 mediates ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2320.