Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor

Nat Commun. 2016 Apr 29;7:11457. doi: 10.1038/ncomms11457.

Abstract

Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.

Publication types

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

MeSH terms

  • Arginine / metabolism
  • Asparagine / metabolism*
  • Aspartate-Ammonia Ligase / genetics*
  • Aspartate-Ammonia Ligase / metabolism
  • Biological Transport
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Culture Media / chemistry
  • Culture Media / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Glutamine / metabolism*
  • HeLa Cells
  • Histidine / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics*
  • Multiprotein Complexes / genetics*
  • Multiprotein Complexes / metabolism
  • Nucleotides / biosynthesis
  • Serine / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Culture Media
  • Multiprotein Complexes
  • Nucleotides
  • Glutamine
  • Serine
  • Histidine
  • Asparagine
  • Arginine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Aspartate-Ammonia Ligase