The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis

Tian-Xiang Wang,Jun-Yun Liang,Cheng Zhang,Yue Xiong,Hai-Xin Yuan,Kun-Liang Guan

doi:10.1038/s41419-019-1984-4

Abstract

Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent lipid peroxidation and is implicated in several human pathologies, such as tissue ischemia, neurodegeneration, and cancer. Ferroptosis appears to be high cell-context dependent and the regulation of ferroptosis by physiological or pathological conditions are unclear. Here, we report that tumor-derived IDH1 mutation sensitizes cells to ferroptosis. Deletion of the mutant IDH1 allele in IDH1 heterozygous tumor cells or pharmacological inhibition of mutant IDH1 to produce the oncometabolite D-2-hydroxyglutarate (D-2-HG) confers resistance to erastin-induced ferroptosis. Conversely, ectopic expression of mutant IDH1 or treatment of cells with cell-permeable D-2-HG promotes the accumulation of lipid reactive oxygen species (ROS) and subsequently ferroptosis. Mechanistically, mutant IDH1 reduces the protein level of the glutathione peroxidase 4 (GPX4), a key enzyme in removing lipid ROS and ferroptosis, and promotes depletion of glutathione. Our results uncover a new role of mutant IDH1 and 2-HG in ferroptosis.

Highlights

Ferroptosis is a recently identified non-apoptotic form of regulated cell death that is prone to happen in tumor cells bearing Ras gene mutation[1] or highly transformed tumor cells[2]
Mutant IDH1 promotes erastin-induced ferroptosis HT-1080 is a model cell line extensively used for ferroptosis study because of its high sensitivity to ferroptosis-inducing compounds, such as erastin and RSL325
We discover that the IDH1 mutation borne by HT-1080 cells, a model cell line commonly used for ferroptosis studies, contributes to the high sensitivity of HT-1080 cells to ferroptosis-inducing agent

Summary

Introduction

Ferroptosis is a recently identified non-apoptotic form of regulated cell death that is prone to happen in tumor cells bearing Ras gene mutation[1] or highly transformed tumor cells[2]. It is believed that excessive accumulation of lipid peroxide (lipid ROS), generated by the family of lipoxygenases, is a critical cause leading to ferroptosis[4]. This links ferroptosis with the breakdown of cellular redox homeostasis maintained by glutathione and glutathione peroxidase 4 (GPX4), the only enzyme in mammalian cells that could eliminate lipid ROS using reduced glutathione (GSH) as a substrate. Compounds that inhibit the lipoxygenases such as Nordihydroguaiaretic acid (NDGA) and zileuton are effective in suppressing ferroptosis[5]. Compounds that inhibit cystine-glutamate antiporter (system Xc–) and subsequently lower GSH level (such as erastin) or that inhibit GPX4 activity (such as RSL3) strongly induce ferroptosis

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Conclusion