Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells

FEBS J. 2021 Dec;288(23):6683-6699. doi: 10.1111/febs.16111. Epub 2021 Jul 27.

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.

Keywords: aspartate; colorectal cancer; metabolomics; mutant KRAS; quantitative proteomics; urea cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Argininosuccinate Synthase / genetics
  • Argininosuccinate Synthase / metabolism
  • Aspartic Acid / genetics*
  • Aspartic Acid / metabolism
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / genetics
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / metabolism
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic*
  • Gene Ontology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Metabolomics / methods
  • Mutation*
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • Proteomics / methods
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • Aspartic Acid
  • Proto-Oncogene Proteins p21(ras)
  • PCK1 protein, human
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • PCK2 protein, human
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Argininosuccinate Synthase
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
  • ASNS protein, human