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; Matthew G. Vander Heiden

doi:10.1038/s41467-019-13419-4

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, Matthew G. Vander Heiden^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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.

Original language	English (US)
Article number	5604
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13419-4
State	Published - Dec 1 2019

Funding

We thank all members of the Vander Heiden lab, Isaac Harris, and Robert J. Downey for thoughtful discussion and advice. We also thank Genya Frenkel and Kendall Condon for assistance with the hypoxia experiment and Lukas Murmann for help with linear algebra. This work was supported by the Ludwig Center for Molecular Oncology Fund (A.L.), NSF GRFP DGE-1122374 (A.L.; K.L.A.; S.M.D.) and T32GM007287 (A.L.; K.L.A.; S.M.D.; A.M.H). E.F. was supported by United States Department of Defense Peer-Reviewed Medical Research Program grant W81XWH-15-1. R.J.D. acknowledges support from the Howard Hughes Medical Institute, a Cancer Prevention and Research Institute of Texas RP160089, and the National Cancer Institute (R35CA220449). M.G.V.H. acknowledges support from a Faculty Scholar grant from the Howard Hughes Medical Institute, SU2C, the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT, and the NIH (R01CA201276, R01CA168653, and P30CA14051).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-13419-4

Cite this

Luengo, A., Abbott, K. L., Davidson, S. M., Hosios, A. M., Faubert, B., Chan, S. H., Freinkman, E., Zacharias, L. G., Mathews, T. P., Clish, C. B., DeBerardinis, R. J., Lewis, C. A., & Vander Heiden, M. G. (2019). Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer. Nature communications, 10(1), Article 5604. https://doi.org/10.1038/s41467-019-13419-4

@article{e7a2b1e0ddb946c7a9e352c7daca25a5,

title = "Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer",

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.",

author = "Alba Luengo and Abbott, {Keene L.} and Davidson, {Shawn M.} and Hosios, {Aaron M.} and Brandon Faubert and Chan, {Sze Ham} and Elizaveta Freinkman and Zacharias, {Lauren G.} and Mathews, {Thomas P.} and Clish, {Clary B.} and DeBerardinis, {Ralph J.} and Lewis, {Caroline A.} and {Vander Heiden}, {Matthew G.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13419-4",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85076145094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076145094&partnerID=8YFLogxK

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 -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this