Caspase-Independent Cell Death by Arsenic Trioxide in Human Cervical Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-12, Vol.64 (24), p.8960-8967
• Main Authors: Kang, Young-Hee, Yi, Min-Jung, Kim, Min-Jung, Park, Moon-Taek, Bae, Sangwoo, Kang, Chang-Mo, Cho, Chul-Koo, Park, In-Chul, Park, Myung-Jin, Rhee, Chang Hun, Hong, Seok-Il, Chung, Hee Yong, Lee, Yun-Sil, Lee, Su-Jae
• Format: Article
• Language: eng ; jpn
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-1830

Although mechanisms of arsenic trioxide (As2O3)-induced cell death have been studied extensively in hematologic cancers, those in solid cancers have yet to be clearly defined. In this study, we showed that the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus is required for As2O3-induced cell death in human cervical cancer cells. We also showed that reactive oxygen species (ROS)-mediated poly(ADP-ribose) polymerase-1 (PARP-1) activation is necessary for AIF release from mitochondria. The treatment of human cervical cancer cells with As2O3 induces dissipation of mitochondrial membrane potential (Δψm), translocation of AIF from mitochondria to the nucleus, and subsequent cell death. Small interfering RNA targeting of AIF effectively protects cervical cancer cells against As2O3-induced cell death. As2O3 also induces an increase of intracellular ROS level and a marked activation of PARP-1. N-acetyl-l-cystein, a thiol-containing antioxidant, completely blocks As2O3-induced PARP-1 activation, Δψm loss, nuclear translocation of AIF from mitochondria, and the consequent cell death. Furthermore, pretreatment of 1,5-dihydroxyisoquinoline or 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, PARP-1 inhibitors, effectively attenuates the loss of Δψm, AIF release, and cell death. These data support a notion that ROS-mediated PARP-1 activation signals AIF release from mitochondria, resulting in activation of a caspase-independent pathway of cell death in solid tumor cells by As2O3 treatment.