Inhibition of isoprenoid biosynthesis induces apoptosis in human promyelocytic HL-60 cells.
Protein isoprenylation is a posttranslational modification that facilitates membrane association and biological activity of a number of proteins. Mevalonate is the precursor of cellular sterols as well as of isoprenoid lipids involved in protein modification. In this study we show that HL-60 cells treated with lovastatin, an inhibitor of mevalonate synthesis, exhibit alterations in growth and morphology, as well as changes in the subcellular distribution of isoprenylated proteins like nuclear lamin A and p21Ras. Moreover, they are induced to die via apoptosis, as evidenced by the appearance of a typical DNA fragmentation pattern. Lovastatin-induced DNA fragmentation can be specifically prevented by mevalonate. The failure of several products of the mevalonate pathway, including cholesterol, to overcome lovastatin effect, points to the involvement of isoprenylated proteins in the mechanisms suppressing cell death.
Pérez-Sala
D
D
Centro de Investigaciones Biológicas, C.S.I.C., Madrid, Spain.
Mollinedo
F
F
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D019821:Simvastatin; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D008148:Lovastatin; D019821:Simvastatin; D008798:Mevalonic Acid; D013936:Thymidine