De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues

Teresa W.M. Fan, Ronald C. Bruntz, Ye Yang, Huan Song, Yelena Chernyavskaya, Pan Deng, Yan Zhang, Parag P. Shah, Levi J. Beverly, Zhen Qi, Angela L. Mahan, Richard M. Higashi, Chi V. Dang, Andrew N. Lane

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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 [13C6]glucose, D2-glycine, [13C2]glycine, and D3-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, [13C6]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 D3-Ser was preferentially incorporated into purine rings over D2-glycine in both tissues and cell lines. MYC suppression attenuated [13C6]glucose, D3-serine, and [13C2]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.

Original languageEnglish
Pages (from-to)13464-13477
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number36
DOIs
StatePublished - Sep 6 2019

Bibliographical note

Publisher Copyright:
© 2019 Fan et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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