Glutamine Addiction and Therapeutic Strategies in Lung Cancer

Abstract

Lung cancer cells are well-documented to rewire their metabolism and energy production networks to support rapid survival and proliferation. This metabolic reorganization has been recognized as a hallmark of cancer. The increased uptake of glucose and the increased activity of the glycolytic pathway have been extensively described. However, over the past years, increasing evidence has shown that lung cancer cells also require glutamine to fulfill their metabolic needs. As a nitrogen source, glutamine contributes directly (or indirectly upon conversion to glutamate) to many anabolic processes in cancer, such as the biosynthesis of amino acids, nucleobases, and hexosamines. It plays also an important role in the redox homeostasis, and last but not least, upon conversion to α-ketoglutarate, glutamine is an energy and anaplerotic carbon source that replenishes tricarboxylic acid cycle intermediates. The latter is generally indicated as glutaminolysis. In this review, we explore the role of glutamine metabolism in lung cancer. Because lung cancer is the leading cause of cancer death with limited curative treatment options, we focus on the potential therapeutic approaches targeting the glutamine metabolism in cancer.

Keywords: Lung cancer; glutamine; glutaminolysis; metabolism; pathways; targeted treatment.

Figure 1

Glutamine metabolism in cancer cells. ALT, alanine aminotransferase; ASCT2, alanine-serine-cysteine-transporter-2; AST, aspartate aminotransferase; CTH, cystathionine gamma-lyase; EAA, essential amino acids; GLS, glutaminase; GLUD, glutamate dehydrogenase; GLUT, glucose transporter; GSH, reduced glutathione; GSHR, glutathione reductase; GSSG, oxidized glutathione; IDH, isocitrate dehydrogenase; α-KG, α-ketoglutarate; LAT1, ʟ-type amino acid transporter; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; MDH, malate dehydrogenase; ME, malic enzyme; MPC, mitochondrial pyruvate carrier; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NH₄⁺, free ammonia; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PG, phosphoglycerate; SAM, S-adenosylmethionine; SLC7A11, solute carrier family member 7A11 (xCT). Glutaminolysis in pink.

Figure 2

Targeting glutamine metabolism. ALT, alanine aminotransferase; ASCT2, alanine-serine-cysteine-transporter-2; AST, aspartate aminotransferase; BCH, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; BPTES, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide; EAA, essential amino acids; EGCG, epigallocatechin-3-gallate; GLS, glutaminase; GLUD, glutamate dehydrogenase; GPNA, ʟ-glutamyl-p-nitroanilide; α-KG, α-ketoglutarate; LAT1, ʟ-type amino acid transporter; L-DON, 6-diazo-5-oxo-ʟ-norleucine; MPC, mitochondrial pyruvate carrier; OAA, oxaloacetate; SLC7A11, solute carrier family member 7A11 (xCT).