期刊
NATURE CHEMICAL BIOLOGY
卷 12, 期 6, 页码 452-U118出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2070
关键词
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资金
- Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation [DRG-112-12]
- Department of Defense Breast Cancer Research Program Postdoctoral Fellowship [BC120208]
- ASTRO Resident Seed Grant [RA-2011-1]
- Susan G. Komen for the Cure
- EMBO Long-Term Fellowship
- NIH [1 R03 DA034602-01A1]
- Stewart Trust
Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
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