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Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer

Oncogene volume 36, pages 3915–3924 (2017)Cite this article

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Abstract

Increased glucose consumption is a hallmark of cancer cells. The increased consumption and subsequent metabolism of glucose during proliferation creates the need for a constant supply of NAD, a co-factor in glycolysis. Regeneration of the NAD required to support enhanced glycolysis has been attributed to the terminal glycolytic enzyme, lactate dehydrogenase (LDH). However, loss of glucose carbons to biosynthetic pathways early in glycolysis reduces the carbon supply to LDH. Thus, alternative routes for NAD regeneration must exist to support the increased glycolytic rate while allowing for the diversion of glucose to generate biomass and support proliferation. Here we demonstrate, using a variety of cancer cell lines as well as activated primary T cells, that cytosolic malate dehydrogenase 1 (MDH1) is an alternative to LDH as a supplier of NAD. Moreover, our results indicate that MDH1 generates malate with carbons derived from glutamine, thus enabling utilization of glucose carbons for glycolysis and for biomass. Amplification of MDH1 occurs at an impressive frequency in human tumors and correlates with poor prognosis. Together, our findings suggest that proliferating cells rely on both MDH1 and LDH to replenish cytosolic NAD, and that therapies designed at targeting glycolysis must consider both dehydrogenases.

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Acknowledgements

We thank Drs David Sabatini and Kivanc Birsoy for the MDH1 KO Jurkat cells, and Hong-Duk Youn for the MDH1 construct. We would also like to thank Todd Rappe and University of Minnesota Nuclear Magnetic Resonance Core for help with nuclear magnetic resonance analysis. We are grateful to Dr David Bernlohr, Michael Downey, Yan Yan and Dr Jenna Benson for stimulating discussions. We also thank Drs Lucas Sullivan and Sandra Armstrong for valuable suggestions. This study was supported by a Seed Grant and an Infrastructure grant from the University of Minnesota Academic Health Center (to AK), National Institutes of Health (NIH) grant R01 CA157971, P/F grant, 3002751553, through the NIH-funded RCMC in Michigan (to AK), and by T32 training fellowship, CA009138, and F31 award, CA177119 (to EAH). The study utilized Metabolomics Core Services supported by grant U24 DK097153 of NIH Common Funds Project to the University of Michigan.

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Author notes

  1. X H Lowman

    Present address: 4Current address: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, CA, USA.,

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    E A Hanse, X H Lowman & A Kelekar

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    E A Hanse, X H Lowman & A Kelekar

  3. Michigan Regional Comprehensive Metabolomics Research Core, University of Michigan, Ann Arbor, MI, USA

    C Ruan, M Kachman & D Wang

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  1. E A Hanse
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Correspondence to A Kelekar.

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Hanse, E., Ruan, C., Kachman, M. et al. Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer. Oncogene 36, 3915–3924 (2017). https://doi.org/10.1038/onc.2017.36

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