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. Copyright 2004 Wiley-Liss, Inc.