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 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.
Herrero-Martin
Griselda
G
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Cientificas, Avda Américo Vespucio s/n, Sevilla, Spain.
López-Rivas
Abelardo
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D017368:Protein Prenylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D020169:Caspases; D002784:Cholesterol; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases