De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues
| Autor: | Ye Yang, Ronald C. Bruntz, Teresa W.-M. Fan, Levi J. Beverly, Yan Zhang, Chi V. Dang, Pan Deng, Zhen Qi, Parag P. Shah, Angela Mahan, Richard M. Higashi, Andrew N. Lane, Yelena Chernyavskaya, Huan Song |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Purine 030102 biochemistry & molecular biology Cell Biology Metabolism Biochemistry Serine De novo synthesis 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Biosynthesis Glycine Nucleotide Purine metabolism Molecular Biology |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| Popis: | Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for de novo biosynthesis are not defined in human cancer tissues. We have employed multiplexed stable isotope-resolved metabolomics to track the metabolism of [(13)C(6)]glucose, D(2)-glycine, [(13)C(2)]glycine, and D(3)-serine into purine nucleotides in freshly resected cancerous and matched noncancerous lung tissues from nonsmall cell lung cancer (NSCLC) patients, and we compared the metabolism with established NSCLC PC9 and A549 cell lines in vitro. Surprisingly, [(13)C(6)]glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the noncancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D(3)-Ser was preferentially incorporated into purine rings over D(2)-glycine in both tissues and cell lines. MYC suppression attenuated [(13)C(6)]glucose, D(3)-serine, and [(13)C(2)]glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose–to–serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for de novo nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy. |
| Databáze: | OpenAIRE |
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