1. Inhibition of Anaplerotic Glutaminolysis Underlies Selenite Toxicity in Human Lung Cancer.
- Author
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Bruntz RC, Belshoff AC, Zhang Y, Macedo JKA, Higashi RM, Lane AN, and Fan TW
- Subjects
- A549 Cells, Antineoplastic Agents pharmacology, Autophagy drug effects, Cell Proliferation drug effects, Citric Acid Cycle drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Glucose metabolism, Glutamic Acid genetics, Glutamic Acid metabolism, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Metabolic Networks and Pathways genetics, Oxidative Stress drug effects, Reactive Oxygen Species metabolism, Glutaminase genetics, Lung Neoplasms drug therapy, Metabolomics, Selenious Acid pharmacology
- Abstract
Large clinical trials and model systems studies suggest that the chemical form of selenium dictates chemopreventive and chemotherapeutic efficacy. Selenite induces excess ROS production, which mediates autophagy and eventual cell death in non-small cell lung cancer adenocarcinoma A549 cells. As the mechanisms underlying these phenotypic effects are unclear, the clinical relevance of selenite for cancer therapy remains to be determined. The authors' previous stable isotope-resolved metabolomics and gene expression analysis showed that selenite disrupts glycolysis, the Krebs cycle, and polyamine metabolism in A549 cells, potentially through perturbed glutaminolysis, a vital anaplerotic process for proliferation of many cancer cells. Herein, the role of the glutaminolytic enzyme glutaminase 1 (GLS1) in selenite's toxicity in A549 cells and in patient-derived lung cancer tissues is investigated. Using [
13 C6 ]-glucose and [13 C5 ,15 N2 ]-glutamine tracers, selenite's action on metabolic networks is determined. Selenite inhibits glutaminolysis and glutathione synthesis by suppressing GLS1 expression, and blocks the Krebs cycle, but transiently activates pyruvate carboxylase activity. Glutamate supplementation partially rescues these anti-proliferative and oxidative stress activities. Similar metabolic perturbations and necrosis are observed in selenite-treated human patients' cancerous lung tissues ex vivo. The results support the hypothesis that GLS1 suppression mediates part of the anti-cancer activity of selenite both in vitro and ex vivo., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2019
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