title: Arsenic trioxide sensitizes CD95/Fas-induced apoptosis through ROS-mediated upregulation of CD95/Fas by NF-kappaB activation.
abstract: CD95/Fas is a cell surface protein that belongs to the tumor necrosis factor receptor family. Signals through CD95/Fas are able to induce apoptosis in sensitive cells. Therefore, modalities to regulate the CD95/Fas expression level in tumor cells are called for. In the present study, we show that sublethal doses of arsenic trioxide (As2O3) sensitized CD95/Fas-induced apoptosis in human cervical cancer cells, and the sensitizing effects resulted from As2O3-mediated increase in the expression of the CD95/Fas. N-acetyl-L-cysteine, a specific scavenger of reactive oxygen species, abrogated As2O3-induced upregulation of CD95/Fas and enhancement of CD95/Fas-mediated apoptosis. Furthermore, inhibition of NF-kappaB by transient transfection of IkappaBalpha supersurppessor blocked the increase of CD95/Fas expression following As2O2 treatment. Antisense oligonucleotide of CD95/Fas and ZB4, an antibody that blocks the binding of CD95/Fas ligand to CD95/Fas, reduced the amount of As2O3-sensitized CD95/Fas-induced apoptosis, demonstrating the specificity of CD95/Fas-binding ligands in the As2O3-sensitized CD95/Fas-induced apoptosis. These findings demonstrate that sensitization of human cervical cancer cells to CD95/Fas-mediated apoptosis by As2O3 can be partly due to induction of ROS and subsequent upregulation of CD95/Fas gene expression by NF-kappaB activation.
authors.affiliation: Laboratory of Cell Biology, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Hyung-Chahn
authors.initials: HC
authors.lastname: Lee
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: Sin-Ae
authors.initials: SA
authors.lastname: Park
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Cho
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ho-Shin
authors.initials: HS
authors.lastname: Gwak
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Hong
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Rhee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis* / Q000494:pharmacology*; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000473:pathology*; D019014:fas Receptor / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D017382:Reactive Oxygen Species; D019014:fas Receptor; D000077237:Arsenic Trioxide