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Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis.
Cancer Lett. 2018 03 01; 416:124-137.CL

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.

Authors+Show Affiliations

Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. Electronic address: t27602@mail.cmuh.org.tw.Department of Animal Science, National Chung Hsing University, Taichung 40227, Taiwan.Department of Animal Science, National Chung Hsing University, Taichung 40227, Taiwan.Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40447, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40447, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29274359

Citation

Chang, Ling-Chu, et al. "Heme Oxygenase-1 Mediates BAY 11-7085 Induced Ferroptosis." Cancer Letters, vol. 416, 2018, pp. 124-137.
Chang LC, Chiang SK, Chen SE, et al. Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Lett. 2018;416:124-137.
Chang, L. C., Chiang, S. K., Chen, S. E., Yu, Y. L., Chou, R. H., & Chang, W. C. (2018). Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Letters, 416, 124-137. https://doi.org/10.1016/j.canlet.2017.12.025
Chang LC, et al. Heme Oxygenase-1 Mediates BAY 11-7085 Induced Ferroptosis. Cancer Lett. 2018 03 1;416:124-137. PubMed PMID: 29274359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. AU - Chang,Ling-Chu, AU - Chiang,Shih-Kai, AU - Chen,Shuen-Ei, AU - Yu,Yung-Luen, AU - Chou,Ruey-Hwang, AU - Chang,Wei-Chao, Y1 - 2017/12/20/ PY - 2017/07/01/received PY - 2017/12/12/revised PY - 2017/12/17/accepted PY - 2017/12/24/pubmed PY - 2018/10/23/medline PY - 2017/12/24/entrez KW - BAY 11–7085 KW - Ferroptosis KW - Glutathione KW - Heme oxygenase-1 KW - Reactive oxygen species SP - 124 EP - 137 JF - Cancer letters JO - Cancer Lett. VL - 416 N2 - 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. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/29274359/Heme_oxygenase_1_mediates_BAY_11_7085_induced_ferroptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(17)30797-8 DB - PRIME DP - Unbound Medicine ER -