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

Reactive Oxygen Species-Mediated Poly(ADP-ribose) Polymerase-1 Activation Signals Apoptosis-Inducing Factor Release from Mitochondria

¹ Laboratory of Radiation Effect and ² Laboratory of Cell Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; and ³ Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea

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 (_m), 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, _m 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 _m, 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.

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