Abstract 449: Catabolism of GSH by GGT supports cancer cell survival

Abstract

Abstract Cancer metabolism depends on amino acid sources to fuel tumor growth and drug resistance. Using amino acid restriction to treat tumors can enhance existing therapeutic techniques. The tripeptide Glutathione (GSH), which contains cysteine, glutamate, and glycine, is often considered an antioxidant, and its potential as an amino acid pool has been overlooked. GSH is ubiquitous in the tumor microenvironment and could provide a ready source of amino acids to tumor cells through its catabolism by the enzyme γ-Glutamyl transpeptidase (GGT), which has been shown to cleave GSH and its’ conjugates in the extracellular space. It is unclear if the cleavage of GSH by GGT supports cancers in vivo. We find that inhibiting GGT with the pharmacologic agent GGsTop blocks GSH catabolism and decreases tumor growth. We show that cultured cells can be rescued from a lethal depletion of cystine upon supplementation with GSH or its catabolic product cysteinylglycine, but not under the conditions of GGT inhibition. Through pharmacokinetic methods, we identify a usable systemic dose of GGsTop and show GGT inhibition in tumor tissue. Further, we demonstrate that systemic GGT inhibition in vivo decreases tumor mass and volume. These findings support the hypothesis that GSH catabolism by GGT1 is a non-canonical source of amino acids for tumor metabolism. Understanding GSH catabolism by GGT could elucidate new metabolic pathways in tumors. Inhibiting GSH catabolism could provide new therapeutic approaches to inhibit tumor growth. Citation Format: Marco Zocchi, Fabio Hecht Castro Medeiros, Fatemeh Alimohammadi, Emily Tuttle, Gloria Asantewaa, TashJae Scales, Isaac S. Harris. Catabolism of GSH by GGT supports cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 449.