Figure 1. Glutamine metabolism. Cancer cells are dependent on specific metabolic pathways, such as glutamine metabolism, to supply excess energy that sustains cell growth and proliferation and to maintain cellular redox balances.

(I) In a normal glutamine (Gln) metabolic pathway, Gln is transported from the cytoplasm to the mitochondria, where it is converted by glutaminase (GLS) into glutamate (Glu). Glu processing by glutamate dehydrogenase 1 (GLUD1) creates a-ketoglutarate (a-KG), which is used by the tricarboxylic acid (TCA) pathway for aerobic production of energy for the cell.

(II[a]) In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic K-Ras downregulates GLUD1, which decreases the cancer cells' use of and dependence on the normal Gln pathway.

(II[b]) In an alternative pathway, Glu is converted to aspartic acid (Asp) within the mitochondria by glutamic-oxaloacetic transaminase 2 (GOT2) and then transported to the cytoplasm. Oncogenic K-Ras also upregulates GOT1, a cytoplasmic enzyme that converts Asp to oxaloacetic acid (OAA).

(II[c]) In a downstream series of reactions by malate dehydrogenase 1 (MDH1) and NADP-dependent malic enzyme (ME1), OAA is converted to pyruvate, which reduces NADP+ to NADPH. This effect decreases reactive oxygen species within the cancer cells to allow growth and survival.

Inhibition of any of the enzymes in the cancer-upregulated Gln pathway results in increased reactive oxygen species and prevents cancer cell growth.