Arsenic trioxide sensitizes CD95/Fas‐induced apoptosis through ROS‐mediated upregulation of CD95/Fas by NF‐κB activation

• Published in: International journal of cancer Vol. 112; no. 4; pp. 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: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 20.11.2004; Wiley-Liss
• Subjects: Antineoplastic agents; apoptosis; arsenic trioxide; Biological and medical sciences; CD95/Fas; General aspects; Medical sciences; NF‐κB; Pharmacology. Drug treatments; reactive oxygen species; Tumors; Antineoplastic agent; Human; Reactive oxygen species; Arsenic trioxide; Malignant tumor; Gene expression; In vitro; Hela cell line; Biological activity; Female genital diseases; Cancerology; Cell death; Established cell line; Fas Antigen; Sensitization; Transcription factor NFκB; Uterine cervix diseases; Cervical cancer; Apoptosis
• 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‐κB by transient transfection of IκBα 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‐κB activation. © 2004 Wiley‐Liss, Inc.