Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells

Abstract

A general feature of cancer metabolism is ATP regeneration via substrate-level phosphorylation even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer the inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. Here, we show that a beneficial aspect of aerobic glycolysis is that it reduces metabolic heat generation during ATP regeneration. 13C-metabolic flux analysis of 12 cultured cancer cell lines and in silico metabolic simulation revealed that metabolic heat production during ATP regeneration via aerobic glycolysis was considerably lesser than that produced via oxidative phosphorylation. The dependency on aerobic glycolysis was partly alleviated upon culturing under low temperatures. In conclusion, thermogenesis is required for maintaining thermal homeostasis and can govern aerobic glycolysis in cancer cells.

Lactate shuttling as an allostatic means of thermoregulation in the brain

“…A recent investigation aimed to explore the Warburg effect from the perspective of metabolic thermogenesis. Using 13 C-metabolic flux analysis of 12 cultured cancer cell lines combined with in silico metabolic simulations, Okahashi et al (2023) present evidence that point to a reduction in metabolic heat production as a potential explanation for the increased reliance on glycolytic metabolism in cancer. In light of the evidence for lactate shuttling in cancer cells (e.g., Sonveaux et al, 2008;Goodwin et al, 2015) and the results of the present work, mitigating metabolic heat via intercellular lactate and/or pyruvate (Hong et al, 2016) exchange and metabolism among cancer cells with elevated demands for ATP seems plausible.…”