DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
- 12 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 593 (7860), 586-590
- https://doi.org/10.1038/s41586-021-03539-7
Abstract
Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1,2,3,4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-l-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate—the substrate and product of dihydroorotate dehydrogenase (DHODH)—attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.This publication has 47 references indexed in Scilit:
- Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunctionBioscience Reports, 2013
- A ratiometric fluorescent probe for assessing mitochondrial phospholipid peroxidation within living cellsFree Radical Biology & Medicine, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal TumorigenesisCancer Cell, 2010
- A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondriaFree Radical Biology & Medicine, 2008
- Role of FIP200 in cardiac and liver development and its regulation of TNFα and TSC–mTOR signaling pathwaysThe Journal of cell biology, 2006
- Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc − cystine transporter: a new action for an old drugLeukemia, 2001
- Import into Mitochondria of Phospholipid Hydroperoxide Glutathione Peroxidase Requires a Leader SequenceBiochemical and Biophysical Research Communications, 1996
- Multicenter phase II study of brequinar sodium in patients with advanced lung cancerCancer Chemotherapy and Pharmacology, 1993
- Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neckCancer Chemotherapy and Pharmacology, 1992