Targeting Glutamine Metabolism for Cancer Treatment

Abstract

Rapidly proliferating cancer cells require energy and cellular building blocks for their growth and ability to maintain redox balance. Many studies have focused on understanding how cancer cells adapt their nutrient metabolism to meet the high demand of anabolism required for proliferation and maintaining redox balance. Glutamine, the most abundant amino acid in plasma, is a well-known nutrient used by cancer cells to increase proliferation as well as survival under metabolic stress conditions. In this review, we provide an overview of the role of glutamine metabolism in cancer cell survival and growth and highlight the mechanisms by which glutamine metabolism affects cancer cell signaling. Furthermore, we summarize the potential therapeutic approaches of targeting glutamine metabolism for the treatment of numerous types of cancer.

Keywords: Anaplerosis; Cancer; Glutamine; Redox homeostasis.

Fig. 1.

Glutamine provides a nitrogen and carbon source in biosynthetic pathways. Glutamine enters the cells via the SLC1A5 transporter and contributes to nucleotide biosynthesis directly or is converted to glutamate by GLS. Glutamate is converted to α-ketoglutarate by either GLUD or aminotransferases. Malate from the TCA cycle can be exported to the cytoplasm and converted to pyruvate and generate NAPDH by ME. Oxaloacetate can be converted to aspartate, which supports amino acid and nucleotide synthesis. Glutamine-derived α-ketoglutarate can provide an alternative carbon source for the formation of acetyl-CoA required for lipid synthesis via reductive carboxylation. Glucose-6-P: glucose-6-phosphate, GLS: glutaminase, GLUD: glutamate dehydrogenase, ME: malic enzyme.

Fig. 2.

Glutamine regulates reactive oxidative stress. Glutamine contributes to the generation of GSH, a tripeptide of glutamate, glycine, and cysteine. Glutamate reacts with cysteine to produce GSH via GLCL/GCLC. Glycine is added during the second step of de novo GSH synthesis via GSS. GSH directly eliminates ROS through the action of GPX. NADPH is required for the regeneration of the reduced form of GSH by GSR. GSH: reduced glutathione, GLCL: glutamate-cysteine ligase catalytic subunit, GCLM: glutamate-cysteine ligase modifier subunit, GSS: glutathione synthetase, GPX: glutathione peroxidase, GSR: glutathione reductase, GSSG: oxidized glutathione.

Fig. 3.

Glutamine regulates mTORC1 activation. Glutamine activates mTORC1 through the simultaneous efflux of leucine into cells by the bidirectional transporter, SLC7A5. Imported leucine binds to Sestrin2 and disrupts the Sestrin2-GATOR2 interaction, resulting in the recruitment of mTORC1 to lysosomes. Glutamine-derived α-ketoglutarate can directly stimulate lysosomal localization and activation of mTORC1. mTORC1: mechanistic target of the rapamycin complex 1.