DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

ABSTRACT: 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^lo

SUBMITTER: Mao C 

PROVIDER: S-EPMC8895686 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature