Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells.
OBJECTIVE
The incidence and mortality rates from esophageal adenocarcinoma (EAC) are rapidly increasing in the western world. Chemoprevention is being advocated to reduce the burden of disease. Statins are used clinically to treat hypercholesterolemia, and have an excellent safety profile. Statins reduce the intracellular availability of several biosynthetic intermediates important in intracellular signaling. We hypothesized that statins may effect EAC proliferation or apoptosis.


METHODS
The OE33 and BIC-1 EAC cell lines and simvastatin, lovastatin, and pravastatin were studied. Proliferation was quantified by thiazoyl blue colormetric and bromodeoxyuridine incorporation assays. Apoptosis was determined using assays for intracellular nucleosomes and caspase-3 activity. Detection of phosphorylated kinases, affinity precipitation, immunoblotting, and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to determine the effects on intracellular signaling.


RESULTS
All three statins reduced viable cell number and inhibited proliferation in a similar dose-dependent manner. Statins induced apoptosis and enhanced the antiproliferative effect of NS-398, a selective cyclooxygenase (COX)-2 inhibitor. The effects were dependent on farnesylation, but not geranylgeranylation, of intracellular targets, and statins reduced serum-stimulated Ras activity . Simvastatin inhibited activation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) but not c-Jun NH(2)-terminal kinase or p38 mitogen-activated protein (MAP) kinase. Statin treatment increased messenger RNA (mRNA) and protein expression of the proapoptotic proteins Bax and Bad, but protein levels of the antiapoptotic proteins B-cell lymphoma (Bcl)-2 and Bcl-X(L) were unchanged.


CONCLUSIONS
Statins inhibit proliferation and induce apoptosis in EAC cells via inhibition of Ras farnesylation and inhibition of the ERK and Akt signaling pathways. Statins may have some potential as chemopreventative and adjuvant chemotherapeutic agents in EAC.
Ogunwobi
Olorunseun O
OO
Biomedical Research Centre, School of Medicine, Health Policy and Practive, University of East Anglia, Norwich, United Kingdom.
Beales
Ian L P
IL
D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009578:Nitrobenzenes; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D019821:Simvastatin; D011494:Protein Kinases; D053148:Caspase 3; D017035:Pravastatin; D008798:Mevalonic Acid