De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer

Metabolic reprogramming is a hallmark in multiple types of malignancies. Fast-growing cancer cells require facilitated synthesis of essential metabolites and excessive energy production. However, whether they are internally coordinated remains largely unknown. Herein, we found that de novo pyrimidine synthesis enhanced aerobic glycolysis in cancer cells. Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize γ-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. Collectively, our findings provide more insights into the regulation of aerobic glycolysis and a metabolic vulnerability that can be exploited to enhance chemotherapy efficacy in gastric cancer.