The Warburg effect modulates DHODH role in ferroptosis: a review

Abstract

Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs.

miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability

“…As a crucial hallmark of cancer, glucose metabolic reprogramming has been implicated in the malignant transformation of cancers [ 33 , 34 ]. To adapt to environmental pressures or to provide more ATP to maintain rapid growth, tumor cells prefer anaerobic glycolysis, even under normal oxygen conditions; this is called the Warburg effect [ 35 , 36 ]. Glucose-dependent membrane transporter proteins mediate transmembrane diffusion into cells, with over 10 members of the glucose membrane transporter family [ 37 ].…”

A deep insight into ferroptosis in lung disease: facts and perspectives

“…DHODH, located on the inner mitochondrial membrane, is able to catalyze pyrimidine nucleotide synthesis, and its loss of activity leads to the accumulation of lipid peroxides in mitochondria and triggers the development of ferroptosis in GPX4-low expressing cells ( 59 ). DHODH inhibits lipid peroxidation by converting mitochondrial CoQ to CoQH2, unlike FSP1 localized outside the membrane, ectopic expression of FSP1 does not protect cells from ferroptosis ( 60 ). The application of the DHODH inhibitor brequinar inhibited the growth of tumor cells with low GPX4 expression in vitro , and the combined treatment of brequinar and the SLC7A11 inhibitor sulfasalazine abolished the growth of tumor cells with high GPX4 expression ( 61 ).…”

Ferroptosis in hepatocellular carcinoma, from mechanism to effect

“…DHODH, an enzyme widely expressed in the inner mitochondrial membrane, is the fourth catalytic rate-limiting enzyme for de novo pyrimidine synthesis and is involved in the regulation of de novo pyrimidine nucleotide synthesis. DHODH inhibits ferroptosis in the inner mitochondrial membrane by oxidizing dihydroorotic acid to orotic acid and reducing ubiquinone (CoQ) to CoQH2 with antioxidant activity ( 42 ). Therefore, the addition of a DHODH inhibitor such as breqinar increases sensitivity to ferroptosis in the inner mitochondrial membrane, and the inactivation of DHODH induces widespread ferroptosis in cancer cells with low GPX4 expression ( 42 ).…”

“…DHODH inhibits ferroptosis in the inner mitochondrial membrane by oxidizing dihydroorotic acid to orotic acid and reducing ubiquinone (CoQ) to CoQH2 with antioxidant activity ( 42 ). Therefore, the addition of a DHODH inhibitor such as breqinar increases sensitivity to ferroptosis in the inner mitochondrial membrane, and the inactivation of DHODH induces widespread ferroptosis in cancer cells with low GPX4 expression ( 42 ). As shown in recent studies, MnCl 2 can promote the expression of type I interferon by enhancing the phosphorylation levels of STING, TBK1 and IRF3, and then inhibit the expression of DHODH in tumor cells, leading to an increase in mitochondrial ROS and lipid peroxidation, thereby increasing the sensitivity of cells to ferroptosis ( 26 ).…”