Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation

Desler, Claus; Durhuus, Jon Ambæk; Hansen, Thomas Lau; Anugula, Sharath; Zelander, Nadia Thaulov; Bøggild, Sisse; Rasmussen, Lene Juel

doi:10.1016/j.mito.2022.03.005

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…The physical location of DHODH in the inner mitochondrial membrane and the fact that the reduction of DHO to orotate is the only step in pyrimidine biosynthesis to take place inside the mitochondria (in eukaryotes), and not in the cytosol, is unique. 67 Our data demonstrated an increase in transcription of genes involved in oxidative phosphorylation in the setting of DHODH inhibition. Furthermore, the genes driving this effect seemed primarily concentrated in the electron transport chain itself.…”

Section: Discussionmentioning

confidence: 53%

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Sexauer,

Alexe,

Gustafsson

et al. 2023

Blood Advances

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Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.-

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Section: Discussionmentioning

confidence: 53%

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Sexauer,

Alexe,

Gustafsson

et al. 2023

Blood Advances

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“…Low cellular levels of pyrimidines will slow down ribonucleotide reductase (RNR)catalyzed reaction which converts NTPs to dNTPs. This assertion is supported by a significant decrease in dNTPs observed following DHODH inhibition [20]. A recent study reported that ferroptosis could be suppressed by inhibiting RNR [21].…”

Section: Dhodh and Ferroptosismentioning

confidence: 81%

The Warburg effect modulates DHODH role in ferroptosis: a review

Amos

et al. 2023

Cell Commun Signal

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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.

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“…DHODH also exhibits a remarkable synergistic interaction with mitochondrial GPX4, working in concert to mitigate lipid peroxidation and forestall ferroptosis within the mitochondrial inner membrane ( 47 , 48 ). DHODH holds a pivotal position in the biosynthetic pathway of pyrimidine nucleotides, playing a crucial role in the production of DNA and RNA ( 49 ), Inhibition of DHODH disrupts this pathway, leading to abnormalities in, or cessation of, pyrimidine nucleotide synthesis. This, in turn, results in a decrease in pyrimidine nucleotide availability, halting the purine-pyrimidine pairing process and ultimately impeding RNA synthesis ( 50 ).…”

Section: Molecular Mechanism and Pathway Of Ferroptosismentioning

confidence: 99%

Inhibition of FSP1: A new strategy for the treatment of tumors (Review)

Dai,

Wei,

Zhao

et al. 2024

Oncol Rep

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Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation

Cited by 6 publications

References 46 publications

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

The Warburg effect modulates DHODH role in ferroptosis: a review

Inhibition of FSP1: A new strategy for the treatment of tumors (Review)

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