Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis. (1st March 2018)

• Record Type: Journal Article
• Authors: Chang, Ling-Chu; Chiang, Shih-Kai; Chen, Shuen-Ei; Yu, Yung-Luen; Chou, Ruey-Hwang; Chang, Wei-Chao
• Is Part Of: Cancer letters. Volume 416(2018)
• Page Start: 124
• Page End: 137
• Publication Date: 2018-03-01
• Subjects: BAY 11–7085 -- Ferroptosis -- Reactive oxygen species -- Glutathione -- Heme oxygenase-1; 7-AAD 7-aminoactinomycin D -- BAY BAY 11–7085 -- BiP binding immunoglobulin protein -- CHOP CCAAT/enhancer-binding protein (C/EBP) homologous protein -- DFO deferoxamine -- DTT dithiothreitol -- ER endoplasmic reticulum -- FBS fetal bovine serum -- GBM glioblastoma multiforme -- GPx4 glutathione peroxidase 4 -- GSH glutathione -- GSSG oxidized l-glutathione -- HO heme oxygenase -- KEAP1 Kelch-like ECH-associated protein 1 -- LIP labile iron pool -- βMe β-mercaptoethanol -- NAC N-acetyl-l-cysteine -- Nrf2 nuclear factor-E2-related factor 2 -- PBS phosphate-buffered saline -- PERK ER stress-related protein double-stranded RNA-dependent protein kinase-like ER kinase -- ROS reactive oxygen species -- SAS sulfasalazine -- SLC7A11 solute carrier family 7 membrane 11 -- ZnPP zinc protoporphyrin-9; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.12.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. 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. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2−SLC7A11−HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. 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. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2−SLC7A11−HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status. Highlights: BAY 11–7085 induces ferroptotic cell death regardless of IκBα−NF-κB signaling. BAY 11–7085 triggers ferroptosis through a Nrf2−SLC7A11−HO-1 signaling pathway. HO-1 mediates redox regulation of ferroptotic death. HO-1 causes endoplasmic reticulum stress and mitophagy.