The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation

Curr Biol. 2014 Oct 6;24(19):2274-80. doi: 10.1016/j.cub.2014.08.007. Epub 2014 Sep 11.

Abstract

Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5' untranslated region (5'UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN.

Publication types

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

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Eukaryotic Initiation Factors / genetics*
  • Eukaryotic Initiation Factors / metabolism
  • Glutaminase / metabolism
  • Glutamine / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mitochondria / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Phosphorylation
  • Real-Time Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Eukaryotic Initiation Factors
  • MYCBP protein, human
  • Multiprotein Complexes
  • Transcription Factors
  • eIF-4B
  • Glutamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Glutaminase