Rapamycin inhibits IGF-1-mediated up-regulation of MDM2 and sensitizes cancer cells to chemotherapy

PLoS One. 2013 Apr 30;8(4):e63179. doi: 10.1371/journal.pone.0063179. Print 2013.


The Murine Double Minute 2 (MDM2) protein is a key regulator of cell proliferation and apoptosis that acts primarily by inhibiting the p53 tumor suppressor. Similarly, the PI3-Kinase (PI3K)/AKT pathway is critical for growth factor-mediated cell survival. Additionally, it has been reported that AKT can directly phosphorylate and activate MDM2. In this study, we show that IGF-1 up-regulates MDM2 protein levels in a PI3K/AKT-dependent manner. Inhibition of mTOR by rapamycin or expression of a dominant negative eukaryotic initiation factor 4E binding protein 1 (4EBP1) mutant protein, as well as ablation of eukaryotic initiation factor 4E (eIF4E), efficiently abolishes IGF-1-mediated up-regulation of MDM2. In addition, we show that rapamycin effectively inhibits MDM2 expression and sensitizes cancer cells to chemotherapy. Taken together, this study reveals a novel mechanism by which IGF-1 activates MDM2 via the mTOR pathway, and that pharmacologic inhibition of mTOR combined with chemotherapy may be more effective in treatment of a subset of cancers harboring increased MDM2 activation.

Publication types

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

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Up-Regulation / drug effects*


  • Antibiotics, Antineoplastic
  • Insulin-Like Growth Factor I
  • Doxorubicin
  • Proto-Oncogene Proteins c-mdm2
  • TOR Serine-Threonine Kinases
  • Sirolimus