Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis

被引：432

作者：

Chang, Ling-Chu ^{[1
,2
]}

Chiang, Shih-Kai ^{[3
]}

Chen, Shuen-Ei ^{[3
]}

Yu, Yung-Luen ^{[4
,5
,6
]}

Chou, Ruey-Hwang ^{[4
,5
,6
]}

Chang, Wei-Chao ^{[5
]}

机构：

[1] China Med Univ Hosp, Chinese Med Res & Dev Ctr, 2 Yude Rd, Taichung 40447, Taiwan

[2] China Med Univ, Dept Biol Sci & Technol, Taichung 40402, Taiwan

[3] Natl Chung Hsing Univ, Dept Anim Sci, Taichung 40227, Taiwan

[4] China Med Univ, Grad Inst Biomed Sci, Taichung 40447, Taiwan

[5] China Med Univ Hosp, Ctr Mol Med, Taichung 40447, Taiwan

[6] Asia Univ, Dept Biotechnol, Taichung 41354, Taiwan

来源：

CANCER LETTERS | 2018年 / 416卷

关键词：

BAY; 11-7085; Ferroptosis; Reactive oxygen species; Glutathione; Heme oxygenase-1; OXIDATIVE STRESS; CELL-DEATH; DYNAMIC EQUILIBRIUM; IRON TRANSPORT; ER STRESS; MITOCHONDRIA; INHIBITORS; APOPTOSIS; PROTEIN; DEGRADATION;

D O I：

10.1016/j.canlet.2017.12.025

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 lam inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-kappa B-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 SLC7All attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 over expression 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. (C) 2017 Elsevier B.V. All rights reserved.

引用

页码：124 / 137

页数：14

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