Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E

Cancer Cell. 2010 Mar 16;17(3):249-61. doi: 10.1016/j.ccr.2010.01.021.

Abstract

We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology
  • Cell Cycle Proteins
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Eukaryotic Initiation Factor-4E / physiology
  • Eukaryotic Initiation Factors
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphoma / metabolism
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Phosphoproteins / metabolism*
  • Phosphoproteins / physiology
  • Phosphorylation
  • Protein Biosynthesis
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / physiology
  • Ribosomal Protein S6 / metabolism
  • T-Lymphocytes / physiology
  • TOR Serine-Threonine Kinases

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Ribosomal Protein S6
  • ribosomal protein S6, mouse
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt