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

Research Article

Maurice Israël ¹ * and Laurent Schwartz ²

¹ Institut Alfred Fessard CNRS, 2 Av.Terrasse, 91190 Gif sur Yvette, France
² Assistance Publique des Hôpitaux de Paris, 3 Av. Victoria, 75004, Paris, France

*Corresponding author: Maurice Israël, 2 Av. Aristide Briand, 91440 Bures sur Yvette, France.
E-mail: mauisrael@wanadoo.fr

Citation: Maurice Israël and Laurent Schwartz (2020) The metabolic rewiring observed in cancer renders tumor cells dependent of ketone bodies and vulnerable to SCOT. Endocrinol Diabetes Metab J Volume 4(1): 1–13 (2020).

Received Date: Dec 16, 2019; Accepted Date: Dec 23, 2019; Published Date: Jan 11, 2020

Copyright: © 2020 Maurice Israël and Laurent Schwartz. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 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.
Differentiated tissues resistant to insulin, but responding to glucagon, adequately provide these ketone bodies. The enzyme, Succinyl-CoA: 3-oxoacid-CoA transferase (SCOT) is specific to ketolysis producing acetyl CoA. Its inhibition deprives tumor cell mitochondria of acetyl CoA, which should hamper tumor development. Inhibiting also the cytosolic acetyl CoA synthetase that tumor cells use for feeding their lipid synthesis should block the tumor.

Keywords: Endocrine pancreas, tumor cell metabolism, Ketone bodies dependency, SCOT inhibition, Acetyl CoA synthetase inhibition.

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