Serine promotes the progression of esophageal cancer through regulating one-carbon metabolism

Abstract

Abstract Serine metabolism provides important metabolic intermediates that support rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotide and NADPH synthesis, which inducing by inhibition of one-carbon metabolism. Mechanistically, aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite for de novo synthesis of purine nucleotides, accumulated during serine starvation, activated 5’-AMP-activated kinase (AMPK), and then inhibited the mTORC1 pathway by directly phosphorylating Raptor at Ser792. Conversely, p53-p21 mediated G1 phase cell cycle arrest induced by DNA oxidative damage and Activating transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1), which in turn promoted compensatory endogenous serine synthesis, which maintained cell survival in serine starvation. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed tumor growth in vitro and in vivo. Taken together, our findings demonstrate a novel mechanism by which serine supports the proliferation of ESCC via one-carbon metabolism to synthesize NADPH and purine nucleotide, which maintaining the mTORC1 activation. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.