The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

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 PHGDH^high 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.