PMID- 17121917
OWN - NLM
STAT- MEDLINE
DCOM- 20070215
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 5
IP  - 11
DP  - 2006 Nov
TI  - Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt 
      signaling and sensitize p53-deficient cells to cytostatic drugs.
PG  - 2706-15
AB  - 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.
FAU - Roudier, Emilie
AU  - Roudier E
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 
      Stockholm, Sweden. ulla.stenius@ki.se.
FAU - Mistafa, Oras
AU  - Mistafa O
FAU - Stenius, Ulla
AU  - Stenius U
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chromones)
RN  - 0 (Heptanoic Acids)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Pyrroles)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - A0JWA85V8F (Atorvastatin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - KXO2KT9N0G (Pravastatin)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Atorvastatin
MH  - Carcinoma, Hepatocellular/metabolism
MH  - Cell Proliferation/drug effects
MH  - Chromones/metabolism/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Etoposide/pharmacology
MH  - Heptanoic Acids/pharmacology
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Liver Neoplasms/metabolism
MH  - Morpholines/metabolism/pharmacology
MH  - Phosphorylation/drug effects
MH  - Pravastatin/pharmacology
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism
MH  - Pyrroles/pharmacology
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
EDAT- 2006/11/24 09:00
MHDA- 2007/02/16 09:00
CRDT- 2006/11/24 09:00
PHST- 2006/11/24 09:00 [pubmed]
PHST- 2007/02/16 09:00 [medline]
PHST- 2006/11/24 09:00 [entrez]
AID - 5/11/2706 [pii]
AID - 10.1158/1535-7163.MCT-06-0352 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2006 Nov;5(11):2706-15. doi: 10.1158/1535-7163.MCT-06-0352.