Caspase activation is accelerated by the inhibition of arsenite-induced, membrane rafts-dependent Akt activation

Khaled Hossain; Anwarul A Akhand; Yoshiyuki Kawamoto; Jun Du; Kozue Takeda; Jianghong Wu; Motoi Yoshihara; Hideo Tsuboi; Masashi Kato; Haruhiko Suzuki; Izumi Nakashima

doi:10.1016/s0891-5849(02)01359-x

Caspase activation is accelerated by the inhibition of arsenite-induced, membrane rafts-dependent Akt activation

Free Radic Biol Med. 2003 Mar 1;34(5):598-606. doi: 10.1016/s0891-5849(02)01359-x.

Authors

Khaled Hossain¹, Anwarul A Akhand, Yoshiyuki Kawamoto, Jun Du, Kozue Takeda, Jianghong Wu, Motoi Yoshihara, Hideo Tsuboi, Masashi Kato, Haruhiko Suzuki, Izumi Nakashima

Affiliation

¹ Department of Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

PMID: 12614848
DOI: 10.1016/s0891-5849(02)01359-x

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androstadienes / pharmacology
Apoptosis / drug effects*
Arsenites / pharmacology*
Carcinogens / metabolism
Caspases / metabolism*
Cholesterol / metabolism
Cyclodextrins / metabolism
Electrophoresis, Polyacrylamide Gel
Enzyme Activation / drug effects
Enzyme Inhibitors / pharmacology*
GTP-Binding Proteins / metabolism
Glycogen Synthase Kinases / metabolism
Humans
Immunoblotting
Jurkat Cells / drug effects
Jurkat Cells / enzymology
Jurkat Cells / metabolism
Membrane Microdomains / metabolism*
Pertussis Toxin / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Poly(ADP-ribose) Polymerases / metabolism
Precipitin Tests
Protein Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Signal Transduction / drug effects
Sodium Compounds / pharmacology*
Sulfhydryl Reagents
Wortmannin
beta-Cyclodextrins*

Substances

Androstadienes
Arsenites
Carcinogens
Cyclodextrins
Enzyme Inhibitors
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins
Sodium Compounds
Sulfhydryl Reagents
beta-Cyclodextrins
sodium arsenite
Cholesterol
Poly(ADP-ribose) Polymerases
Pertussis Toxin
Glycogen Synthase Kinases
AKT1 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Caspases
GTP-Binding Proteins
betadex
Wortmannin