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

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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.
Funding Information
  • MEXT | Japan Society for the Promotion of Science (KAKENHI (17K19606, 16H04730, 17H05534, and 17H06011), KAKENHI (18H05215 and 25221303))
  • MEXT | Japan Science and Technology Agency (CREST (JPMJCR15G4))
  • Japan Agency for Medical Research and Development (P-CREATE (19cm0106105h0004))