Glutaminolysis as a target for cancer therapy

Abstract

Cancer cells display an altered metabolic circuitry that is directly regulated by oncogenic mutations and loss of tumor suppressors. Mounting evidence indicates that altered glutamine metabolism in cancer cells has critical roles in supporting macromolecule biosynthesis, regulating signaling pathways, and maintaining redox homeostasis, all of which contribute to cancer cell proliferation and survival. Thus, intervention in these metabolic processes could provide novel approaches to improve cancer treatment. This review summarizes current findings on the role of glutaminolytic enzymes in human cancers and provides an update on the development of small molecule inhibitors to target glutaminolysis for cancer therapy.

Figure 1

Glutaminolysis in cancer cells. Glutamine is transported through transporters (i.e., SLC1A5 and SLC7A5) to enter the glutaminolysis pathway. Enzymes in the glutaminolysis pathway suggested to be potential anticancer targets are shown in blue and inhibitors of these enzymes are listed in red. Dotted arrows show transcription factors involved in the regulation of relevant enzymes. α-KG, α-ketoglutarate; ASCT2, ASC amino acid transporter 2; AOA, aminooxyacetate; BCH, 2- aminobicyclo(2,2,1)-heptane-2-carboxylic acid; BPTES, bis-2-[5–phenylacetamido-1, 2, 4-thiadiazol-2-yl] ethyl sulfide; DON, 6-diazo-5-oxo-l-norleucine; EGCG, epigallocatechin gallate; GDH1, glutamate dehydrogenase 1; GLS, glutaminase; GOT2, glutamate oxaloacetate transaminase 2; GPNA, γ-l-glutamyl-p-nitroanilide; GPT2, glutamate pyruvate transaminase 2; LAT1, L-type amino acid transporter 1.