Aerobic glycolysis in cancer cells supplies ATP while preventing excess metabolic thermogenesis

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.