Targeting Mnks for cancer therapy

Oncotarget. 2012 Feb;3(2):118-31. doi: 10.18632/oncotarget.453.

Abstract

Deregulation of protein synthesis is a common event in human cancer and a key player in translational control is eIF4E. Elevated expression levels of eIF4E promote cancer development and progression. Recent findings suggest that eIF4E activity is a key determinant of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK mediated tumorigenic activity and targeting eIF4E should have a major impact on these pathways in human cancer. The function of eIF4E is modulated through phosphorylation of a conserved serine (Ser209) by Mnk1 and Mnk2 downstream of ERK. While the phosphorylation event is necessary for oncogenic transformation, it seems to be dispensable for normal development. Hence, pharmacologic Mnk inhibitors may provide non-toxic and effective anti-cancer strategy. Strong circumstantial evidence indicates that Mnk inhibition presents attractive therapeutic potential, but the lack of selective Mnk inhibitors has so far confounded pharmacological target validation and clinical development.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sequence Alignment
  • TOR Serine-Threonine Kinases / metabolism
  • raf Kinases / metabolism
  • ras Proteins / metabolism

Substances

  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • MKNK1 protein, human
  • MTOR protein, human
  • MKNK2 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins