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.
Although mechanisms of arsenic trioxide (As(2)O(3))-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 As(2)O(3)-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 As(2)O(3) induces dissipation of mitochondrial membrane potential (Deltapsi(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 As(2)O(3)-induced cell death. As(2)O(3) 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 As(2)O(3)-induced PARP-1 activation, Deltapsi(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 Deltapsi(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 As(2)O(3) treatment.
Kang
Young-Hee
YH
Laboratory of Radiation Effect and Laboratory of Cell Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Yi
Min-Jung
MJ
Kim
Min-Jung
MJ
Park
Moon-Taek
MT
Bae
Sangwoo
S
Kang
Chang-Mo
CM
Cho
Chul-Koo
CK
Park
In-Chul
IC
Park
Myung-Jin
MJ
Rhee
Chang Hun
CH
Hong
Seok-Il
SI
Chung
Hee Yong
HY
Lee
Yun-Sil
YS
Lee
Su-Jae
SJ
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor; D001152:Arsenicals / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002712:Chlorides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D005260:Female; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D001152:Arsenicals; D002712:Chlorides; D005420:Flavoproteins; D008565:Membrane Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C050510:arsenic trichloride; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D000111:Acetylcysteine