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

Author

Listed:
  • Alba Luengo

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Keene L. Abbott

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Shawn M. Davidson

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard University)

  • Aaron M. Hosios

    (Massachusetts Institute of Technology
    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
    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
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Caroline A. Lewis

    (Massachusetts Institute of Technology)

  • Matthew G. Vander Heiden

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard University
    Dana-Farber Cancer Institute)

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.

Suggested Citation

  • 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. DeBerar, 2019. "Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13419-4
    DOI: 10.1038/s41467-019-13419-4
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    Cited by:

    1. Gloria Asantewaa & Emily T. Tuttle & Nathan P. Ward & Yun Pyo Kang & Yumi Kim & Madeline E. Kavanagh & Nomeda Girnius & Ying Chen & Katherine Rodriguez & Fabio Hecht & Marco Zocchi & Leonid Smorodints, 2024. "Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Tuo Ji & Lihua Zheng & Jiale Wu & Mei Duan & Qianwen Liu & Peng Liu & Chen Shen & Jinling Liu & Qinyi Ye & Jiangqi Wen & Jiangli Dong & Tao Wang, 2023. "The thioesterase APT1 is a bidirectional-adjustment redox sensor," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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