Glutamine addiction and therapeutic strategies in pancreatic cancer

Figure 1 Metabolism of glutamine in pancreatic cancer. Glutamine enters the cells through four receptors (SLC1, SLC6, SLC7, and SLC38) and can be incorporated into various metabolic pathways either as a nitrogen source or as a carbon source, which is important for the synthesis of nucleotides, non-essential amino acids, glucosamine and gluconeogenesis, the tricarboxylic acid (TCA) cycle, and glutathione metabolism. Under normal physiological conditions, glutamine can be converted to α-ketoglutarate by canonical pathway to replenish the TCA cycle metabolites, which is differ from the non-canonical pathway of glutamine using in pancreatic cancer. TCA: Tricarboxylic acid; αKG: α-ketoglutarate; GOT1: Aspartate transaminase; OAA: Oxaloacetate; GLUD1: Glutamate dehydrogenase; NEAAs: Non-essential amino acids.

Figure 2 Glutamine metabolic reprogramming. Glutamine is a key nutrient in tumourgenesis and Glutamine metabolic reprogramming in pancreatic cancer help enhance metabolic use of glutamine in cancer cells. Pancreatic cancer cells affect glutamate metabolism through Myc, Kras mutations, regulated in DNA damage and development 1, p53, Protein arginine methyltransferase 4, Ras transform, β-catenin/TCF 7 complex. REDD1: Regulated in DNA damage and development 1; ROS: Reactive oxygen species; GLS: Glutaminase; mTOR: the mammalian target of rapamycin; MDH1: Malate dehydrogenase 1; GSH: Glutathione.

Figure 3 Targeting glutamine metabolism in pancreatic cancer. A few compounds that target glutamine metabolism by inhibiting glutaminase 1, Ivosidenib (AG-120) or aspartate transaminase (GOT1), blocking activity of alanine-serine-cysteine transporter 2 (ASCT2), ASCT2 knockdown, affecting Kas/c-Myc are studied for the treatment of pancreatic cancer. ROS: Reactive oxygen species; GLS: Glutaminase; BPTES: Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide; AO: Aspulvinone O; mTOR: Mammalian target of rapamycin; IDH1: Isocitrate dehydrogenase.