A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer

Abstract

Glucose metabolism is remodeled in cancer, but the global pattern of cancer-specific metabolic changes remains unclear. Here we show, using the comprehensive measurement of metabolic enzymes by large-scale targeted proteomics, that the metabolism both carbon and nitrogen is altered during the malignant progression of cancer. The fate of glutamine nitrogen is shifted from the anaplerotic pathway into the TCA cycle to nucleotide biosynthesis, with this shift being controlled by glutaminase (GLS1) and phosphoribosyl pyrophosphate amidotransferase (PPAT). Interventions to reduce the PPAT/GLS1 ratio suppresses tumor growth of many types of cancer. A meta-analysis reveals that PPAT shows the strongest correlation with malignancy among all metabolic enzymes, in particular in neuroendocrine cancer including small cell lung cancer (SCLC). PPAT depletion suppresses the growth of SCLC lines. A shift in glutamine fate may thus be required for malignant progression of cancer, with modulation of nitrogen metabolism being a potential approach to SCLC treatment.

A second Warburg‐like effect in cancer metabolism: The metabolic shift of glutamine‐derived nitrogen

“…[33] Cancer cells thus use glutamine to synthesize aspartate. [18,33] Glutamic-oxaloacetic transaminase 1 (GOT1), a cytosolic enzyme, synthesizes intracellular aspartate by transferring the nitrogen of glutamate to oxaloacetate (Figure 2A). [30,31,34] The F I G U R E 3 Tumor carbon metabolism is dependent on glucose oxidation rather than on glutaminolysis in vivo.…”

“…[45] Metabolic flux analysis of glucose and glutamine in cancer cells, performed by direct measurement in vivo, recently revealed that glycolysis serves as a major carbon-replenishing pathway for the TCA cycle in a variety of cancer types, including non-small cell lung cancer and glioblastoma ( Figure 3A). [18,[45][46][47][48][49][50][51] Lactate produced from glucose is released into the extracellular space, from where it is taken up by cancer cells and used for replenishment of the TCA cycle. [49,50] Whereas lung cancer cells in monolayer culture in vitro tend to use glutamine as a substrate for the TCA cycle, they use glucose instead of glutamine in the tumor microenvironment in vivo, a situation in which glutamine uptake by cancer cells is extremely limited.…”

“…GLS1 is thus highly expressed in an environment containing a high concentration (∼2 mM) of glutamine, similar to that used for most cell experiments in vitro, whereas its expression is markedly suppressed in cells cultured with a physiological glutamine concentration similar to that in plasma (∼0.6 mM) ( Figure 4B). [18,64,65] In contrast, the expression level of c-Myc in various cancer cell types in culture was shown to be increased in the presence of a physiological glutamine concentration compared with that of a high glutamine concentration…”

“…Excessive activity of GLS1 results in depletion of cytosolic glutamine and suppresses the proliferation of cancer cells by reducing the supply of nitrogen for de novo nucleotide biosynthesis. [18] Conversely, pharmacologic inhibition of GLS1 activity in cancer cells has been shown to substantially increase the size of the intracellular glutamine pool, [69][70][71] and to attenuate inhibition of cancer cell proliferation under the condition of glutamine deprivation. [18,62] Ammonia is a basic and diffusible metabolite that is able to cross cell membranes, and which also inhibits the growth of cancer cells.…”

“…[3,9] The shift in glutamine-derived nitrogen metabolism from glutaminolysis to the de novo nucleotide biosynthesis pathway, as well as the Warburg effect, a mechanism of glucose derived carbon metabolism, is a cancer-specific and universal metabolic phenotype that contributes to the malignant evolution of cancer. [18] In this review, we summarize what is known of the mechanism responsible for regulation of the fate of glutamine-derived nitrogen and its contribution to the malignant evolution of cancer. We also address the possibility of developing a novel therapeutic strategy for recalcitrant cancers, especially small cell lung cancer (SCLC), that is based on modulation of a metabolic shift in glutamine-derived nitrogen.…”