The metabolic rewiring observed in cancer renders tumor cells dependent of ketone bodies and vulnerable to SCOT inhibition

Abstract

The finding that autoantibodies against glutamic acid decarboxylase that synthesizes GABA, provoke Diabetes type I, draws attention on a GABAergic regulation of the endocrine pancreas suppressing catabolic glucagon release if anabolic insulin is liberated; a GABA deficiency would then impair this exclusion mechanism, allowing a release of both hormones. Moreover, the GABA deficiency alters a mechanism terminating insulin release; an insulin leakage renders differentiated cells gradually resistant to insulin, while responding to glucagon. Mitotic cells with new insulin receptors, respond to both hormones, displaying a hybrid metabolic pattern typically found in tumor cells. They cannot get their mitochondrial acetyl CoA from glycolysis, since pyruvate kinase and pyruvate dehydrogenase are OFF, following the glucagon signal. Nor can they form acetyl CoA by the beta-oxidation of fatty acids, since the insulin signal they receive elicits the synthesis of fatty acids, which automatically closes their beta-oxidation. Indeed, malonyl CoA produced along the lipogenic pathway inhibits the mitochondrial carnityl-transporter of fatty acids. Hence, with both the glycolytic and fatty acid sources of mitochondrial acetyl CoA closed, tumor cells can only get their vital mitochondrial acetyl CoA supply from the ketolysis of ketone bodies.