Succinate dehydrogenase activity supports de novo purine synthesis DOI Creative Commons
Mushtaq Ahmad Nengroo, A. Klein,

Heather S. Carr

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation survival, but specific contributions tricarboxylic (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that TCA enzyme succinate dehydrogenase (SDH) essential maintaining optimal normal cancer cells. Genetic or pharmacological inhibition SDH markedly attenuates synthesis, leading a significant reduction cell proliferation. Mechanistically, causes an accumulation succinate, which directly impairs biosynthetic pathway. response, cells compensate by upregulating salvage pathway, adaptation represents potential therapeutic vulnerability. Notably, co-inhibition induces pronounced antiproliferative antitumoral effects preclinical models. These findings only reveal signaling regulating also provide promising strategy targeting dependencies cancer.

Язык: Английский

Succinate dehydrogenase activity supports de novo purine synthesis DOI Creative Commons
Mushtaq Ahmad Nengroo, A. Klein,

Heather S. Carr

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation survival, but specific contributions tricarboxylic (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that TCA enzyme succinate dehydrogenase (SDH) essential maintaining optimal normal cancer cells. Genetic or pharmacological inhibition SDH markedly attenuates synthesis, leading a significant reduction cell proliferation. Mechanistically, causes an accumulation succinate, which directly impairs biosynthetic pathway. response, cells compensate by upregulating salvage pathway, adaptation represents potential therapeutic vulnerability. Notably, co-inhibition induces pronounced antiproliferative antitumoral effects preclinical models. These findings only reveal signaling regulating also provide promising strategy targeting dependencies cancer.

Язык: Английский

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