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Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection

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Abstract

Pyruvate carboxylase (PC), an anaplerotic enzyme, plays an essential role in various cellular metabolic pathways including gluconeogenesis, de novo fatty acid synthesis, amino acid synthesis, and glucose-induced insulin secretion. Deregulation of PC expression or activity has long been known to be associated with metabolic syndrome in several rodent models. Accumulating data in the past decade clearly showed that deregulation of PC expression is associated with type 2 diabetes in humans, while targeted inhibition of PC expression in a mouse model reduced adiposity and improved insulin sensitivity in diet-induced type 2 diabetes. More recent studies also show that PC is strongly involved in tumorigenesis in several cancers, including breast, non-small cell lung cancer, glioblastoma, renal carcinoma, and gall bladder. Systems metabolomics analysis of these cancers identified pyruvate carboxylation as an essential metabolic hub that feeds carbon skeletons of downstream metabolites of oxaloacetate into the biosynthesis of various cellular components including membrane lipids, nucleotides, amino acids, and the redox control. Inhibition or down-regulation of PC expression in several cancers markedly impairs their growth ex vivo and in vivo, drawing attention to PC as an anti-cancer target. PC has also exhibited a moonlight function by interacting with immune surveillance that can either promote or block viral infection. In certain pathogenic bacteria, PC is essential for infection, replication, and maintenance of their virulence phenotype.

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Acknowledgements

This work is supported by the International Research Network (IRN) program, contract no. IRN59W0003 from the Thailand Research Fund. U.L. is supported by a royal golden jubilee PhD program, PHD/0103/2557, the Thailand Research Fund. The authors thank Professor John Wallace for critical reading of the manuscript.

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  1. Gene Expression and Metabolic Science Research Laboratory, Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Udom Lao-On & Sarawut Jitrapakdee

  2. School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia

    Paul V. Attwood

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Correspondence to Sarawut Jitrapakdee.

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Lao-On, U., Attwood, P.V. & Jitrapakdee, S. Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection. J Mol Med 96, 237–247 (2018). https://doi.org/10.1007/s00109-018-1622-0

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