Exogenous and endogenous sources of serine contribute to colon cancer metabolism, growth, and resistance to 5-fluorouracil.

Serine is a non-essential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. Additionally, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer (CRC). In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of CRC cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress CRC xenograft growth and enhance the anti-tumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed anti-tumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to CRC growth and resistance to 5-FU.