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Cell Rep. 2018 Aug 28;24(9):2381-2391.e5. doi: 10.1016/j.celrep.2018.07.086.

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis.

Author information

1
Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
2
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
3
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
4
Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
5
Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address: steven_gygi@hms.harvard.edu.
6
Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Centre for Innovative and Collaborative Health Services Research, IWK Health Centre, Halifax, NS, Canada; Department of Biology, Dalhousie University, Halifax, NS, Canada. Electronic address: shashi.gujar@dal.ca.

Abstract

NAD+ is a key metabolic redox cofactor that is regenerated from nicotinamide through the NAD+ salvage pathway. Here, we find that inhibiting the NAD+ salvage pathway depletes serine biosynthesis from glucose by impeding the NAD+-dependent protein, 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, we find that PHGDHhigh breast cancer cell lines are exquisitely sensitive to inhibition of the NAD+ salvage pathway. Further, we find that PHGDH protein levels and those of the rate-limiting enzyme of NAD+ salvage, NAMPT, correlate in ER-negative, basal-like breast cancers. Although NAD+ salvage pathway inhibitors are actively being pursued in cancer treatment, their efficacy has been poor, and our findings suggest that they may be effective for PHGDH-dependent cancers.

KEYWORDS:

FK866; NAD(+) salvage; PHGDH; breast cancer; complex I; metabolomics; quantitative proteomics; serine biosynthesis

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