Mercuric chloride induces apoptosis via a mitochondrial-dependent pathway in human leukemia cells.
Mercurial compounds modulate immunologic functions by inducing cytotoxicity. Although mercury chloride (HgCl(2)) is known to induce apoptosis in various immune system cells, the mechanism of the induction of apoptosis is poorly understood. In this study, we examined the activation of caspase-3, an important cysteine aspartic protease, during HgCl(2)-induced apoptosis in a human leukemia cell line (HL-60 cells). Both DNA fragmentation, a characteristic of apoptotic cells, and proteolysis of poly(ADP-ribose) polymerase (PARP), a substrate of caspase-3, occurred at 6 h after HgCl(2) treatment in HL-60 cells. These results suggest that the activation of caspase-3 was involved in HgCl(2)-induced apoptosis. The release of cytochrome c (Cyt c) from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was also observed in HgCl(2)-treated HL-60 cells. Moreover, the release of Cyt c from mitochondria was observed in HgCl(2)-treated mitochondria isolated from mice liver, and this was followed by mitochondrial permeability transition (PT). The PT was inhibited by cyclosporin A (CsA), a potent inhibitor of PT. CsA also suppressed the occurrence of DNA fragmentation induced by HgCl(2) treatment in HL-60 cells. Taken together, these findings indicate that HgCl(2) is a potent inducer of apoptosis via Cyt c release from the mitochondria in HL-60 cells.
Araragi
Saeko
S
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Kondoh
Masuo
M
Kawase
Masaki
M
Saito
Sayaka
S
Higashimoto
Minoru
M
Sato
Masao
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002474:Cell-Free System; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000208:ethnology / Q000473:pathology*; D008627:Mercuric Chloride / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D011064:Poly Adenosine Diphosphate Ribose / Q000494:pharmacology
D003574:Cytochrome c Group; D011064:Poly Adenosine Diphosphate Ribose; D008627:Mercuric Chloride