2. Academic Validation
  3. Catabolism of extracellular glutathione supplies amino acids to support tumor growth

Catabolism of extracellular glutathione supplies amino acids to support tumor growth

  • bioRxiv. 2024 Oct 13:2024.10.10.617667. doi: 10.1101/2024.10.10.617667.
Fabio Hecht 1 2 3,  Marco Zocchi 1 2 3,  Emily T Tuttle 1 2,  Nathan P Ward 4,  Bradley Smith 2,  Yun Pyo Kang 4,  Juliana Cazarin 1 2,  Zamira G Soares 1 2,  Mete Emir Ozgurses 5,  Huiping Zhao 5,  Colin Sheehan 6,  Fatemeh Alimohammadi 1 2,  Lila D Munger 1 2,  Dhvani Trivedi 1 2,  Gloria Asantewaa 1 2 7,  Sara K Blick-Nitko 1 2,  Jason J Zoeller 8,  Ying Chen 9,  Vasilis Vasiliou 9,  Bradley M Turner 10,  Alexander Muir 6,  Jonathan L Coloff 5,  Joshua Munger 2 7,  Gina M DeNicola 4,  Isaac S Harris 1 2
Affiliations

Affiliations

  • 1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA, 14620.
  • 2 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA, 14620.
  • 3 These authors contributed equally.
  • 4 Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA, 33612.
  • 5 Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, USA, 60612.
  • 6 Ben May Department of Cancer Research, University of Chicago, Chicago, IL, USA, 60637.
  • 7 Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA, 14642.
  • 8 Department of Cell Biology, Harvard Medical School, Boston, MA, USA, 02115.
  • 9 Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA, 06510.
  • 10 Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA, 14620.
PMID: 39416022 DOI: 10.1101/2024.10.10.617667
Abstract

Restricting Amino acids from tumors is an emerging therapeutic strategy with significant promise. While typically considered an intracellular antioxidant with tumor-promoting capabilities, glutathione (GSH) is a tripeptide of cysteine, glutamate, and glycine that can be catabolized, yielding Amino acids. The extent to which GSH-derived Amino acids are essential to cancers is unclear. Here, we find that GSH catabolism promotes tumor growth. We show that depletion of intracellular GSH does not perturb tumor growth, and extracellular GSH is highly abundant in the tumor microenvironment, highlighting the potential importance of GSH outside of tumors. We find supplementation with GSH can rescue Cancer cell survival and growth in cystine-deficient conditions, and this rescue is dependent on the catabolic activity of γ-glutamyltransferases (GGTs). Finally, pharmacologic targeting of GGTs' activity prevents the breakdown of circulating GSH, lowers tumor cysteine levels, and slows tumor growth. Our findings indicate a non-canonical role for GSH in supporting tumors by acting as a reservoir of Amino acids. Depriving tumors of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with Cancer. Further, these findings change our view of GSH and how Amino acids, including cysteine, are supplied to cells.

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