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

Author

Listed:
  • Manabu Kodama

    (Medical Institute of Bioregulation, Kyushu University)

  • Kiyotaka Oshikawa

    (Medical Institute of Bioregulation, Kyushu University)

  • Hideyuki Shimizu

    (Medical Institute of Bioregulation, Kyushu University)

  • Susumu Yoshioka

    (Medical Institute of Bioregulation, Kyushu University
    LSI Medience Corporation)

  • Masatomo Takahashi

    (Medical Institute of Bioregulation, Kyushu University)

  • Yoshihiro Izumi

    (Medical Institute of Bioregulation, Kyushu University)

  • Takeshi Bamba

    (Medical Institute of Bioregulation, Kyushu University)

  • Chisa Tateishi

    (Medical Institute of Bioregulation, Kyushu University)

  • Takeshi Tomonaga

    (National Institute of Biomedical Innovation, Health, and Nutrition)

  • Masaki Matsumoto

    (Kyushu University)

  • Keiichi I. Nakayama

    (Medical Institute of Bioregulation, Kyushu University
    Kyushu University)

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.

Suggested Citation

  • Manabu Kodama & Kiyotaka Oshikawa & Hideyuki Shimizu & Susumu Yoshioka & Masatomo Takahashi & Yoshihiro Izumi & Takeshi Bamba & Chisa Tateishi & Takeshi Tomonaga & Masaki Matsumoto & Keiichi I. Nakaya, 2020. "A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15136-9
    DOI: 10.1038/s41467-020-15136-9
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