TY - JOUR
T1 - Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer
AU - Luengo, Alba
AU - Abbott, Keene L.
AU - Davidson, Shawn M.
AU - Hosios, Aaron M.
AU - Faubert, Brandon
AU - Chan, Sze Ham
AU - Freinkman, Elizaveta
AU - Zacharias, Lauren G.
AU - Mathews, Thomas P.
AU - Clish, Clary B.
AU - DeBerardinis, Ralph J.
AU - Lewis, Caroline A.
AU - Vander Heiden, Matthew G.
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-13419-4
DO - 10.1038/s41467-019-13419-4
M3 - Article
C2 - 31811141
AN - SCOPUS:85076145094
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5604
ER -