Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells

Peter F. Doubleday, Luca Fornelli, Ioanna Ntai, Neil L. Kelleher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic mutations in the KRAS gene are found in 30–50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.

Original languageEnglish (US)
JournalFEBS Journal
DOIs
StateAccepted/In press - 2021

Keywords

  • aspartate
  • colorectal cancer
  • metabolomics
  • mutant KRAS
  • quantitative proteomics
  • urea cycle

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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