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Metabolic and mind shifts

from glucose to glutamine and acetate addictions in cancer

Corbet, Cyril; Feron, Olivier

Current Opinion in Clinical Nutrition & Metabolic Care: July 2015 - Volume 18 - Issue 4 - p 346–353
doi: 10.1097/MCO.0000000000000178
GENES AND CELL METABOLISM: Edited by Paulo Ivo Homem de Bittencourt Jr. and Philip Newsholme
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Purpose of review Glutamine and acetate were recently identified as alternatives to glucose for fueling the tricarboxylic acid (TCA) cycle in cancer cells, particularly in the context of hypoxia.

Recent findings Molecular mechanisms orchestrating glutamine and acetate metabolism were elicited through the combination of 13C tracer analysis and genetic silencing, or pharmacological modulation of key metabolic enzymes including those converting glutamate into α-ketoglutarate (αKG) (and beyond) and acetate into acetyl-coenzyme A (CoA).

Summary Oxidative decarboxylation and reductive carboxylation of αKG represent two options for the glutamine metabolism. The canonical forward mode of the TCA cycle fuelled by glutamine may benefit from the decarboxylation of malate into pyruvate for fueling pyruvate dehydrogenase and generating acetyl-CoA to offer a self-sustainable TCA cycle. Under hypoxia and mutations in the TCA cycle, the reductive carboxylation of glutamine-derived αKG into citrate mainly supports lipogenesis via the ATP citrate lyase that cleaves citrate into oxaloacetate and acetyl-CoA. Still, a largely unsuspected source of acetyl-CoA was shown to derive from the direct ligation of acetate to CoA by acetyl-CoA synthetases. Altogether, these findings identify critical metabolic nodes in the glutamine and acetate metabolism as new determinants of tumor metabolic plasticity that may facilitate the design of synthetic lethal treatments.

Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium

Correspondence to Professor Olivier Feron, Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 53 avenue E. Mounier, B1.53.09, B-1200 Brussels, Belgium. Tel: +32 2 7645264; fax: +32 2 7645269; e-mail: olivier.feron@uclouvain.be

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