NF-kappaB activation by triphenyltin triggers apoptosis in HL-60 cells.
Trisubstituted organotin pesticides are lethal for different cell types. In this study we investigated whether triphenyltin chloride (TPT) causes apoptosis in HL-60 promyelocytic cells and, if so, by what mechanisms. We report that 5 microM TPT increased intracellular Ca2+ in HL-60 cells within seconds; concomitantly actin depolymerization was detected 30 s and 1 min after the treatment. This was followed 15 min later by NF-kappaB activation, and apoptotic bodies and DNA fragmentation were evident after 3 and 6 h, respectively. At these times TPT also induced the release of tumor necrosis factor-alpha (TNF-alpha). Prior treatment of the cells with a polyclonal antibody to human TNF-alpha abolished TPT-induced DNA fragmentation, which suggests that the ultimate effect of TPT may be mediated by TNF-alpha. Prior treatment of the cells with 100 microM pyrrolidine dithiocarbamate, an antioxidant and potent inhibitor of NF-kappaB activation, prevented actin depolymerization, NF-kappaB activation, and DNA fragmentation, although it did not affect TPT-induced Ca2+ mobilization. These findings suggest that TPT increases intracellular Ca2+, alters actin polymerization and the cytoskeleton, and induces NF-kappaB activation, TNF-alpha synthesis, DNA degradation, and apoptosis. Reactive oxygen species seem to be essential to NF-kappaB activation, TNF-alpha synthesis, and the subsequent steps.
Marinovich
M
M
Laboratory of Toxicology, Institute of Pharmacological Sciences, University of Milan, via Balzaretti 9, Milan, 20133, Italy.
Viviani
B
B
Corsini
E
E
Ghilardi
F
F
Galli
C L
CL
D000199:Actins / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism*; D009947:Organotin Compounds / Q000494:pharmacology*; D011108:Polymers; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000199:Actins; D000975:Antioxidants; D016328:NF-kappa B; D009947:Organotin Compounds; D011108:Polymers; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D004247:DNA; C030665:triphenyltin; D002118:Calcium