Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells
- PMID: 30540938
- PMCID: PMC6302548
- DOI: 10.1016/j.celrep.2018.11.043
Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells
Abstract
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.
Keywords: MCT1; MCT4; cancer; lactate; metformin; synthetic lethality; syrosingopine.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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References
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- Baek G., Tse Y.F., Hu Z., Cox D., Buboltz N., McCue P., Yeo C.J., White M.A., DeBerardinis R.J., Knudsen E.S., Witkiewicz A.K. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 2014;9:2233–2249. - PubMed
-
- Billington R.A., Travelli C., Ercolano E., Galli U., Roman C.B., Grolla A.A., Canonico P.L., Condorelli F., Genazzani A.A. Characterization of NAD uptake in mammalian cells. J. Biol. Chem. 2008;283:6367–6374. - PubMed
-
- Brand A., Singer K., Koehl G.E., Kolitzus M., Schoenhammer G., Thiel A., Matos C., Bruss C., Klobuch S., Peter K. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24:657–671. - PubMed
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