Glutaminases regulate glutathione and oxidative stress in cancer
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REVIEW ARTICLE
Glutaminases regulate glutathione and oxidative stress in cancer José M. Matés1,2 · José A. Campos‑Sandoval1,2 · Juan de los Santos‑Jiménez1,2 · Javier Márquez1,2 Received: 2 July 2020 / Accepted: 8 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Targeted therapies against cancer have improved both survival and quality of life of patients. However, metabolic rewiring evokes cellular mechanisms that reduce therapeutic mightiness. Resistant cells generate more glutathione, elicit nuclear factor erythroid 2-related factor 2 (NRF2) activation, and overexpress many anti-oxidative genes such as superoxide dismutase, catalase, glutathione peroxidase, and thioredoxin reductase, providing stronger antioxidant capacity to survive in a more oxidative environment due to the sharp rise in oxidative metabolism and reactive oxygen species generation. These changes dramatically alter tumour microenvironment and cellular metabolism itself. A rational design of therapeutic combination strategies is needed to flatten cellular homeostasis and accomplish a drop in cancer development. Context-dependent glutaminase isoenzymes show oncogenic and tumour suppressor properties, being mainly associated to MYC and p53, respectively. Glutaminases catalyze glutaminolysis in mitochondria, regulating oxidative phosphorylation, redox status and cell metabolism for tumour growth. In addition, the substrate and product of glutaminase reaction, glutamine and glutamate, respectively, can work as signalling molecules moderating redox and bioenergetic pathways in cancer. Novel synergistic approaches combining glutaminase inhibition and redox-dependent modulation are described in this review. Pharmacological or genetic glutaminase regulation along with oxidative chemotherapy can help to improve the design of combination strategies that escalate the rate of therapeutic success in cancer patients. Keywords GLS · GLS2 · MYC · NRF2 · p53 · Reactive oxygen species
Introduction Organisms living in aerobic conditions and having an oxidative metabolism are constantly subjected to reactive oxygen species (ROS), which alter the signalling pathways and regulate carcinogenesis (Matés et al. 2012a). ROS refers to all molecular oxygen-derived free radicals like superoxide anion radicals (O2·–) and hydroxyl radicals (HO·), as well as the nonradical molecule hydrogen peroxide (H2O2) (Avolio et al. 2020). ROS play different roles on cellular homeostasis in vivo, being involved in energy production, cell José A. Campos-Sandoval and Juan de los Santos-Jiménez contributed equally to this publication. * José M. Matés [email protected] 1
Department of Molecular Biology and Biochemistry, Canceromics Lab, Faculty of Sciences, University of Málaga, Campus de Teatinos, 29071 Málaga, Spain
Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
2
growth and cellular interaction (Scialò et al. 2017). Further, ROS may be highly damaging, as they can attack biological macromolecules as lipids, polysaccharides,
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