mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein

Mol Cell. 2017 Sep 21;67(6):936-946.e5. doi: 10.1016/j.molcel.2017.08.011. Epub 2017 Sep 14.

Abstract

Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth.

MeSH terms

  • Amino Acids / deficiency
  • Amino Acids / metabolism*
  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Energy Metabolism / drug effects*
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Models, Biological
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism
  • Mutation
  • Naphthyridines / pharmacology*
  • Pinocytosis / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / metabolism*
  • Proteolysis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA Interference
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Transfection

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Amino Acids
  • Multiprotein Complexes
  • Naphthyridines
  • Protein Kinase Inhibitors
  • Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)