title: Impairment of Na(+),K(+)-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide.
abstract: Human T-cell leukemia is a malignant disease that needs various regimens of cytotoxic chemotherapy to overcome drug resistance. Recently, Na(+),K(+)-ATPase has emerged as a potential target for cancer therapy. However, its exact signaling pathway in human T-cell leukemia cell death has not been well defined. In the current study, we found CD95(APO-1) was able to trigger the internalization of plasma membrane Na(+),K(+)-ATPase in Jurkat cells or primary T cells as a mechanism to suppress its activity. This internalization was closely relevant to intracellular glutathione (GSH) depletion in Jurkat cells downstream of Fas-associated death domain protein (FADD) and caspase 8. GSH depletion in Fas L-treated Jurkat cells induced the generation of hydrogen peroxide (H(2)O(2)), which subsequently increased the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Exogenous H(2)O(2) even mimicked the effect of Fas L to upregulate the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit and suppress Na(+),K(+)-ATPase activity. Overall, our results indicate that CD95(APO-1) induces the FADD- and caspase 8-dependent internalization of Na(+),K(+)-ATPase through intracellular GSH loss, and the subsequent generation of H(2)O(2)-mediated serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Taken together, this study presents a novel regulatory mechanism of Na(+),K(+)-ATPase in CD95(APO-1)-mediated human T-leukemia cell apoptosis.
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Yin
authors.forename: W
authors.initials: W
authors.lastname: Cheng
authors.forename: W
authors.initials: W
authors.lastname: Shen
authors.forename: L
authors.initials: L
authors.lastname: Shu
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: Z-C
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010042:Ouabain / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D019014:fas Receptor / Q000494:pharmacology*
chemical_list: D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D016877:Oxidants; D019014:fas Receptor; D010042:Ouabain; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione