Arsenic trioxide sensitizes CD95/Fas-induced apoptosis through ROS-mediated upregulation of CD95/Fas by NF- mu B activation

• Published in: International journal of cancer 2004-11, Vol.112 (4), p.596-606
• Main Authors: Woo, Sang Hyeok, Park, In-Chul, Park, Myung-Jin, An, Sungkwan, Lee, Hyung-Chahn, Jin, Hyeon-Ok, Park, Sin-Ae, Cho, Hyeyoung, Lee, Su-Jae, Gwak, Ho-Shin, Hong, Young-Joon, Hong, Seok-Il, Rhee, Chang Hun
• Format: Article
• Language: English
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.20433

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-B by transient transfection of IB supersuppressor blocked the increase of CD95/Fas expression following As2O3 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-B activation.