Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

Mol Cancer Ther. 2006 Nov;5(11):2706-15. doi: 10.1158/1535-7163.MCT-06-0352.

Abstract

Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin- and cytostatic drug-induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR-dependent manner. Statins also induced mTOR-dependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Atorvastatin
  • Carcinoma, Hepatocellular / metabolism
  • Cell Proliferation / drug effects
  • Chromones / metabolism
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Etoposide / pharmacology
  • Heptanoic Acids / pharmacology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Liver Neoplasms / metabolism
  • Morpholines / metabolism
  • Morpholines / pharmacology
  • Phosphorylation / drug effects
  • Pravastatin / pharmacology
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrroles / pharmacology
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Chromones
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Morpholines
  • Pyrroles
  • Tumor Suppressor Protein p53
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Etoposide
  • Atorvastatin
  • Protein Kinases
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Pravastatin