TY - JOUR
T1 - A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer
AU - Kodama, Manabu
AU - Oshikawa, Kiyotaka
AU - Shimizu, Hideyuki
AU - Yoshioka, Susumu
AU - Takahashi, Masatomo
AU - Izumi, Yoshihiro
AU - Bamba, Takeshi
AU - Tateishi, Chisa
AU - Tomonaga, Takeshi
AU - Matsumoto, Masaki
AU - Nakayama, Keiichi I.
N1 - Funding Information:
We thank T. Akagi for the pCX4 system and vectors for hTERT and the SV40 early region; K. Yanagihara for human cancer cell lines (National Cancer Center, Japan); JCRB Cell Bank for SCLC cell lines; T. Takami and K. Tsunematsu for technical assistance; and R. Wakabayashi for discussion on meta-analysis. This work was supported in part by KAKENHI grants from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan to K.I.N. (18H05215 and 25221303) and to M.M. (17K19606, 16H04730, 17H05534, and 17H06011) as well as by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED). M.M. is also supported by Core Research for Evolutionary Science and Technology (CREST, JPMJCR15G4) of the Japan Science and Technology Agency (JST).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15136-9
DO - 10.1038/s41467-020-15136-9
M3 - Article
C2 - 32184390
AN - SCOPUS:85082054494
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1320
ER -
