Induction of apoptosis dependent on caspase activities and growth arrest in HL-60 cells by PGA2.
Prostaglandin (PG) A2 has been reported to inhibit the growth or induce apoptosis of various tumor cells. In the present study, PGA2 inhibited the growth of HL-60 cells and concomitantly-induced nuclear condensation and DNA fragmentation, characteristics of apoptosis. Down-regulation of c-myc mRNA, and activation of caspase-3 were observed in the PGA2 -treated cells. PGA2-induced DNA fragmentation was completely abolished in the presence of zVAD-Fmk or zDEVD-Fmk. But, relative cell survival was not improved up to that of untreated cells by pretreatment of caspase inhibitors, and c-myc down-regulation was not recovered by caspase inhibitors, either. Moreover, cytochrome c release and activation of caspase-9 was also observed in apoptotic cells and a specific inhibitor of caspase-9 (zLEHD-Fmk) prevented both DNA fragmentation and activation of caspase-3, but not relative cell survival, implying the upstream mitochondrial event of caspase-3 activation. In addition, antagonistic Fas antibody (ZB4) exerted no effect on the apoptosis. Taken together, these results suggest that PGA2 may induce the apoptosis as well as growth inhibition in HL-60 cells, and cytochrome c release and caspase activation seem to play a critical role in this apoptosis which might be independent or downstream of growth inhibition associated with c-myc down-regulation.
Kim
Ho-Shik
HS
Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul, South Korea.
Rhim
Hyangshuk
H
Jeong
Seong-Whan
SW
Kim
Jin Woo
JW
Kim
In-Kyung
IK
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D016259:Genes, myc / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D003574:Cytochrome c Group; D009842:Oligopeptides; D011454:Prostaglandins A; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D020169:Caspases; C100008:prostaglandin A2