Arsenic trioxide sensitizes CD95/Fas-induced apoptosis through ROS-mediated upregulation of CD95/Fas by NF-kappaB activation.
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.
Woo
Sang Hyeok
SH
Laboratory of Cell Biology, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Park
In-Chul
IC
Park
Myung-Jin
MJ
An
Sungkwan
S
Lee
Hyung-Chahn
HC
Jin
Hyeon-Ok
HO
Park
Sin-Ae
SA
Cho
Hyeyoung
H
Lee
Su-Jae
SJ
Gwak
Ho-Shin
HS
Hong
Young-Joon
YJ
Hong
Seok-Il
SI
Rhee
Chang Hun
CH
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*
D000970:Antineoplastic Agents; D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D017382:Reactive Oxygen Species; D019014:fas Receptor; D000077237:Arsenic Trioxide