Targeting glutamine metabolism as a therapeutic strategy for cancer

Abstract

Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.

Fig. 1. Interlinked networks involved in glutamine metabolism.

Glutamine transporters (SLC1A5, SLC38A1/SLC38A2, and SLC6A14) expressed on the cell membrane transport glutamine into the cytosol. Next, the SLC1A5 variant transports glutamine to the mitochondrial matrix, where it is converted to glutamate by GLS; this is the rate-limiting step of glutaminolysis. Glutamine-derived glutamate is catalyzed into α-KG by GLUD1, GOT2, and GPT2 to release ammonia, aspartate, and alanine, respectively. Glutamine-derived glutamate in the mitochondria is also transported to the cytosol by SLC25A18/SLC25A22. GOT1, which is part of the malate-aspartate shuttle, contributes to the maintenance of redox homeostasis by converting OAA to aspartate, and GPT1 converts pyruvate to alanine. SLC7A11 transports cysteine to the cytosol in exchange for glutamate. Glutamine-derived glutamate and cysteine are ligated by GCLM/GCLC, which is in turn utilized by GSS to form GSH, which scavenges cellular ROS. Inhibitors of each step of glutamine metabolism are shown in white boxes. GLS, glutaminase; α-KG, α-ketoglutarate; GLUD1, glutamate dehydrogenase 1; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; GCLM, glutamate-cysteine ligase modifier subunit; GCLC, glutamate-cysteine ligase catalytic subunit; GSS, glutathione synthetase; GSH, reduced glutathione; ROS, reactive oxygen species; ASNS, asparagine synthetase; PSAT1, phosphoserine aminotransferase 1.

Fig. 2. Resistance mechanisms used by cancer cells in response to glutamine starvation.

a Glutamine starvation induces metabolic flexibility, in which the influx of glucose-derived pyruvate via MPC and fatty acid-derived acyl-CoA via CPT1 into the mitochondria drives TCA cycle activity. b Under conditions of glutamine deprivation, the tumor suppressor protein p53 induces the expression of the SLC1A3 and SLC7A2 transporters. Aspartate uptake through SLC1A3 transporters increases the amount of malate, which is a TCA cycle intermediate, leading to an increase in oxidative phosphorylation and glutamine synthesis. Aspartate is used for nucleotide synthesis. Arginine uptake through SLC7A3 transporters restores mTORC1 expression, which is suppressed by glutamine depletion. The high level of intracellular asparagine increases the expression of GLUL proteins, thereby increasing glutamine and protein synthesis. c Under conditions of nutrient stress, macropinocytosis internalizes extracellular macromolecules to supply amino acids. Membrane ruffling aids in the uptake of extracellular macromolecules, such as serum albumin, via the formation of macropinosomes. After fusion between macropinosomes and lysosomes, albumin is degraded to supply amino acids to the cytosol and the mitochondrial TCA cycle. d Glutamine deprivation increases the expression of p53 and its target genes (Sestrin2, Gadd45a, and Cdkn1) and increases the phosphorylation of C/EBPβ and its target gene (Sestrin2), all of which maintain energy and redox balance and increase cancer cell survival. MPC, mitochondrial pyruvate carrier; CPT1, carnitine palmitoyltransferase I; TCA, tricarboxylic acid cycle; Asp, aspartate; Arg, arginine; Asn, asparagine; Gln, glutamine; ROS, reactive oxygen species; GLUL, glutamate-ammonia ligase; C/EBPβ, CCAAT/enhancer binding protein β.

Fig. 3. T-cell-mediated immune responses to glutamine-targeted treatment in cancer cells.

a Glutamine deprivation and transporter inhibition decrease glutamine metabolism, thereby boosting EGFR/ERK/c-Jun signaling and calcium/NF-kB signaling, leading to upregulation of PD-L1. PD-L1 suppresses antitumor immune responses by blocking T-cell activation in the tumor microenvironment. b Treatment with glutamine analogs, including DON and JHU-083, decreases glucose and glutamine metabolism, leading to inhibition of tumor growth via a decrease in hypoxia, acidosis, and nutrient depletion in the tumor microenvironment. Furthermore, DON decreases the recruitment of MDSCs by suppressing the secretion of CSF3 by tumor cells and blocking the production of the immunosuppressive metabolite kynurenine; this inhibits the synthesis of the hyaluronan-rich ECM, resulting in the activation and infiltration of T cells. PD-L1, programmed death-ligand 1; CSF3, colony stimulating factor 3; MDSC, myeloid-derived suppressor cell; ECM, extracellular matrix.