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DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
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DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
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Journal Article
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
2021
Overview
Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism
1
–
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 (GPX4
low
). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4
low
cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4
high
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 GPX4
low
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 GPX4
high
tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.
DHO dehydrogenase regulates ferroptosis by preventing mitochondrial lipid peroxidation and its inhibition suppresses growth in tumours with low levels of GPX4.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/109
/ 13/31
/ 13/51
/ 14/19
/ 38/77
/ 45/90
/ 64/60
/ Animals
/ Biphenyl Compounds - pharmacology
/ Cancer
/ Defense
/ Dihydroorotate dehydrogenase
/ Dihydroorotate Dehydrogenase - genetics
/ Dihydroorotate Dehydrogenase - metabolism
/ Enzymes
/ Female
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Mice
/ Phospholipid Hydroperoxide Glutathione Peroxidase - antagonists & inhibitors
/ Phospholipid Hydroperoxide Glutathione Peroxidase - genetics
/ Science
/ Tumors
/ Uridine
