Statins activate a mitochondria-operated pathway of apoptosis in breast tumor cells by a mechanism regulated by ErbB2 and dependent on the prenylation of proteins

Statins are inhibitors of the mevalonate synthesis pathway that induce apoptosis in tumor cells although the apoptotic mechanism activated by statins remains to be elucidated. We have examined the role of the mitochondria-operated pathway of apoptosis in the cell death induced by statins in breast t...

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Bibliographic Details
Published in:FEBS letters 2008-07, Vol.582 (17), p.2589-2594
Main Authors: Herrero-Martin, Griselda, López-Rivas, Abelardo
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis
Bcl-2
Breast Neoplasms - metabolism
Caspases - metabolism
Cell Line, Tumor
Cholesterol - biosynthesis
ErbB2
farnesylpyrophosphate ammonium salt
FPP
geranylgeranylpyrophosphate
GGPP
HMG-CoA
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
hydroxymethylglutaryl-Coenzyme A
Lovastatin - pharmacology
Mitochondria
Mitochondria - metabolism
PARP
poly-(ADP-ribose) polymerase
Prenylation
Protein Prenylation
Proto-Oncogene Proteins c-bcl-2 - metabolism
Receptor, ErbB-2 - metabolism
Statin
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Summary:Statins are inhibitors of the mevalonate synthesis pathway that induce apoptosis in tumor cells although the apoptotic mechanism activated by statins remains to be elucidated. We have examined the role of the mitochondria-operated pathway of apoptosis in the cell death induced by statins in breast tumor cells and its regulation by protein prenylation and ErbB2 overexpression. Lovastatin treatment down-regulates the expression of Bcl-2 and activates apoptosis through a mitochondria-operated, ErbB2- regulated mechanism. Apoptosis induced by statins is independent of their effects on cholesterol synthesis and involves protein prenylation. Our results indicate that prenylation of apoptosis-regulating proteins is a key event in the survival of breast tumor cells and this requirement could be circumvented in cells overexpressing the oncogene ErbB2.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2008.06.034