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

David C. Montrose, Suchandrima Saha, Miguel Foronda, Erin M. McNally, Justin Chen, Xi Kathy Zhou, Taehoon Ha, Jan Krumsiek, Mustafa Buyukozkan, Akanksha Verma, Olivier Elemento, Rhonda K. Yantiss, Qiuying Chen, Steven S. Gross, Lorenzo Galluzzi, Lukas E. Dow, Andrew J. Dannenberg

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Serine is a nonessential 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. In addition, 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. 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 colorectal cancer 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 colorectal cancer xenograft growth and enhance the antitumor 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 antitumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to colorectal cancer growth and resistance to 5-FU. SIGNIFICANCE: These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2275/F1.large.jpg.

Original languageEnglish (US)
Pages (from-to)2275-2288
Number of pages14
JournalCancer research
Issue number9
StatePublished - May 1 2021


  • Aged
  • Animals
  • Antimetabolites, Antineoplastic/administration & dosage
  • Colonic Neoplasms/diet therapy
  • DNA Damage
  • Diet/methods
  • Drug Resistance, Neoplasm/drug effects
  • Female
  • Fluorouracil/administration & dosage
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Middle Aged
  • Pregnancy
  • Serine/deficiency
  • Transaminases/deficiency
  • Treatment Outcome
  • Tumor Burden/drug effects
  • Xenograft Model Antitumor Assays

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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