title: Caspase activation is accelerated by the inhibition of arsenite-induced, membrane rafts-dependent Akt activation.
abstract: Renewed interest in arsenic has been shown recently due to its dual nature of being a potent toxin and a drug for treatment of acute promyelocytic leukemia (APL) because of its ability to trigger caspase activation. Here, we found that sodium arsenite (NaAsO(2)) also triggers the signal for activation of Akt and downstream glycogen synthase 3beta (GSK3beta). Such Akt/GSK3beta activation was abrogated completely by wortmannin, an inhibitor of PI-3 kinase, and greatly by pertussis toxin, a G-protein inhibitor. Arsenite-induced Akt phosphorylation also was inhibited by sequestrating membrane cholesterol with beta cyclodextrin. Reducing reagents/reactive oxygen species (ROS) scavengers reduced arsenite-induced Akt phosphorylation and beta cyclodextrin reduced arsenite-mediated ROS production, suggesting that arsenite-induced G-protein/Akt/GSK3beta pathway is membrane raft dependent and redox linked. We also found that a combination of a low concentration (1 microM) of arsenite and wortmannin triggers the signal for caspase activation, whereas neither of these elements alone did so. These results suggested that selective blockade of the arsenite-provoked PI-3 kinase/Akt pathway can promote the arsenite-triggered pathway for caspase activation, and this may open a new study area for wider applications of arsenic as a drug for treating various kinds of leukemia.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Khaled
authors.initials: K
authors.lastname: Hossain
authors.forename: Anwarul A
authors.initials: AA
authors.lastname: Akhand
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kawamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Kozue
authors.initials: K
authors.lastname: Takeda
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wu
authors.forename: Motoi
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsuboi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Suzuki
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakashima
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000494:pharmacology*; D013439:Sulfhydryl Reagents; D000077191:Wortmannin; D047392:beta-Cyclodextrins
chemical_list: D000730:Androstadienes; D018053:Arsenites; D002273:Carcinogens; D020169:Caspases; D002784:Cholesterol; D003505:Cyclodextrins; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D038341:Glycogen Synthase Kinases; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017670:Sodium Compounds; D013439:Sulfhydryl Reagents; D000077191:Wortmannin; D047392:beta-Cyclodextrins; C017947:sodium arsenite; C494918:AKT1 protein, human; C031215:betadex