Caspase-8 dependent TRAIL-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalase.
TNF-related apoptosis-inducing ligand (TRAIL/ Apo-2L) is a member of the TNF family of apoptosis-inducing proteins that initiates apoptosis in a variety of neoplastic cells while displaying minimal or absent cytotoxicity to most normal cells. Therefore, TRAIL is currently considered a promising target to develop anti-cancer therapies. TRAIL-receptor ligation recruits and activates pro-caspase-8, which in turn activates proteins that mediate disruption of the mitochondrial membranes. These events lead to the nuclear and cytosolic damage characteristic of apoptosis. Here we report that TRAIL-induced apoptosis is mediated by oxidative stress and that vitamin C (ascorbic acid), a potent nutritional antioxidant, protects cancer cell lines from apoptosis induced by TRAIL. Vitamin C impedes the elevation of reactive oxygen species (ROS) levels induced by TRAIL and impairs caspase-8 activation. We found that the removal of hydrogen peroxide by extracellular catalase during TRAIL-induced apoptosis also impairs caspase-8 activation. These data suggest that hydrogen peroxide is produced during TRAIL-receptor ligation, and that the increase of intracellular ROS regulates the activation of caspase-8 during apoptosis. Additionally we propose a mechanism by which cancer cells might resist apoptosis via TRAIL, by the intake of the nutritional antioxidant vitamin C.
Perez-Cruz
Isabel
I
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. iperez@saturn.med.nyu.edu
Cárcamo
Juan M
JM
Golde
David W
DW
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002374:Catalase / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D020014:K562 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D020298:U937 Cells
D061945:Caspase Inhibitors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D002374:Catalase; C505530:CASP8 protein, human; D053181:Caspase 8; D001205:Ascorbic Acid