Inhibition of anaplerotic glutaminolysis underlies selenite toxicity in human lung cancer.

Author(s) Bruntz, R.C.; Belshoff, A.C.; Zhang, Y.; Macedo, J.K.A.; Higashi, R.M.; Lane, A.N.; Fan, T.W.M.
Journal Proteomics
Date Published 2019 Jul 12
Abstract

Large clinical trials and studies in model systems suggest that the chemical form of selenium may dictate chemopreventive and chemotherapeutic efficacy. Selenite induces excess ROS production, which mediates autophagy and eventual cell death in non-small cell lung cancer (NSCLC) adenocarcinoma A549 cells. The exact mechanisms that underlie these phenotypic effects are unclear, thus the clinical relevance of selenite or other selenocompounds for cancer therapy remains to be determined. Using stable isotope-resolved metabolomics (SIRM) and gene expression analysis, we previously showed that selenite simultaneously disrupts glycolysis, the Krebs cycle, and polyamine metabolism in A549 cells, potentially through perturbed glutaminolysis. Glutaminolysis is a vital anaplerotic process for the proliferation and survival of many cancer cells. Here we investigated the role of key glutaminolytic enzyme glutaminase 1 (GLS1) in selenite's toxicity in A549 cells and in patient-derived lung cancer tissue slices. Using [ C ]-glucose and [ C , N ]-glutamine as tracers, we tracked the time course of selenite's action on multiple pathways. We found that selenite inhibited glutaminolysis and glutathione synthesis by suppressing GLS1 expression in addition to blocking the Krebs cycle but transiently activating the pyruvate carboxylase activity. Glutamate supplementation in part rescued these anti-proliferative and oxidative stress activities. Similar metabolic perturbations and tissue necrosis were evident in human patients' cancerous lung tissues in ex vivo experiments with selenite. Altogether, our results support the hypothesis that GLS1 suppression mediates part of the anti-cancer activity of selenite both in vitro and ex vivo. This article is protected by copyright. All rights reserved.

DOI 10.1002/pmic.201800486
ISSN 1615-9861
Citation Bruntz RC, Belshoff AC, Zhang Y, Macedo JK, Higashi RM, Lane AN, et al. Inhibition of anaplerotic glutaminolysis underlies selenite toxicity in human lung cancer. Proteomics. 2019:e1800486.

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