Protective role of cytosolic 2-cys peroxiredoxin in the TNF-alpha-induced apoptotic death of human cancer cells.
Cytosolic 2-cys peroxiredoxin (2-cysPrx) exhibiting thioredoxin-dependent hydroperoxide reductase activity has been demonstrated to be involved in a number of signaling processes, such as receptor tyrosine kinase and MAP kinase activation. However, its role in the cell death pathway has yet to be elucidated. Here we show that cytosolic 2-cysPrx suppresses the TNF-alpha-induced apoptosis of human cervical cancer cells in a caspase-8-dependent manner. The HeLa cervical cancer cells expressing a dominant negative mutant (DN) of a cytosolic 2-cysPrx manifested remarkable increase in intracellular reactive oxygen species level, which was counteracted by catalase administration, and apoptotic cell death induced by combined treatment of TNF-alpha and cycloheximide compared to the control (CT) cells. Similarly, the DN cells were also susceptible to apoptosis induced by the TNF-related apoptosis-inducing ligand. The apoptosis enhanced by DN expression was shown to be dependent on a typical FADD/caspase pathway. The DN cells undergoing apoptosis showed enhanced caspase-8 and -3 activations, as compared to the CT cells. In contrast, there was no difference observed in the sustained JNK activation between CT and DN cells. Thus, this study illustrates that intracellular reactive oxygen species regulated by cytosolic 2-cysPrx is involved in the TNF-alpha-induced apoptotic cell death via controlling caspase activation.
Lee
Joo Young
JY
Division of Life and Pharmaceutical Sciences and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, 127-750, Korea.
Jung
Hyung Jung
HJ
Song
In Sung
IS
Williams
Mark S
MS
Choi
Chulhee
C
Rhee
Sue Goo
SG
Kim
Jiyoung
J
Kang
Sang Won
SW
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D054464:Peroxiredoxins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D054464:Peroxiredoxins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; D053181:Caspase 8