Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells.
Lovastatin, an HMG-CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL-60. However, the mechanisms of lovastatin-induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase-3, but not caspase-1 activity. Lovastatin also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase-3 inhibitors, Ac-DEVD-CHO and Z-VAD-FMK, inhibited lovastatin induced caspase-3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL-60 cells apoptosis through activation of caspase-3 and DNase II activities.
Wang
I K
IK
Institutes of Biochemistry, College of Medicine, National Taiwan University, Taipei.
Lin-Shiau
S Y
SY
Lin
J K
JK
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002458:Cell Fractionation; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004273:DNA, Neoplasm; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D011065:Poly(ADP-ribose) Polymerases; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D008798:Mevalonic Acid