Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer

Alba Luengo, Keene L. Abbott, Shawn M. Davidson, Aaron M. Hosios, Brandon Faubert, Sze Ham Chan, Elizaveta Freinkman, Lauren G. Zacharias, Thomas P. Mathews, Clary B. Clish, Ralph J. DeBerardinis, Caroline A. Lewis and Matthew G. Vander Heiden ()
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Alba Luengo: Massachusetts Institute of Technology
Keene L. Abbott: Massachusetts Institute of Technology
Shawn M. Davidson: Massachusetts Institute of Technology
Aaron M. Hosios: Massachusetts Institute of Technology
Brandon Faubert: University of Texas Southwestern Medical Center
Sze Ham Chan: Massachusetts Institute of Technology
Elizaveta Freinkman: Massachusetts Institute of Technology
Lauren G. Zacharias: University of Texas Southwestern Medical Center
Thomas P. Mathews: University of Texas Southwestern Medical Center
Clary B. Clish: Broad Institute of MIT and Harvard University
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Caroline A. Lewis: Massachusetts Institute of Technology
Matthew G. Vander Heiden: Massachusetts Institute of Technology

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), a byproduct of methylglyoxal detoxification, is elevated in both human and murine non-small cell lung cancers (NSCLC). Methylglyoxal is a reactive metabolite byproduct of glycolysis that reacts non-enzymatically with nucleophiles in cells, including basic amino acids, and reduces cellular fitness. Detoxification of methylglyoxal requires reduced glutathione (GSH), which accumulates to high levels in NSCLC relative to normal lung. Ablation of the methylglyoxal detoxification enzyme glyoxalase I (Glo1) potentiates methylglyoxal sensitivity and reduces tumor growth in mice, arguing that targeting pathways involved in detoxification of reactive metabolites is an approach to exploit the consequences of increased glucose metabolism in cancer.

Date: 2019
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DOI: 10.1038/s41467-019-13419-4

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