Thursday, April 4, 2013
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
(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
(II[b]) In an alternative pathway, Glu is
converted to aspartic
(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
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.