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Cytosolic antioxidant enzyme regulate TNF‐alpha‐induced apoptosis

Tumor necrosis factor α (TNFα) is a pleiotrophic cytokine which induces the activation of NF‐κB, MAP kinases, and cell death. TNF‐α‐induces the programmed cell death under the condition, where NF‐κB activation is defective, concomitant with robust increase of reactive oxygen species (ROS). Therefore, intracellular signaling processes including the inhibition of NF‐κB activation and robust increase of reactive oxygen species (ROS) are prerequisite for the induction of cell death programming. In order to elucidate the molecular mechanisms underlying the involvement of ROS in TNF α‐induced cell death, we targeted cytosolic antioxidant enzymes including catalase, glutathione peroxidase, and peroxiredoxin which are H2O2‐reducing peroxidases. Systematic depletion of cellular H2O2‐reducing peroxidases using RNA interference revealed that ablation of cytosolic antioxidant enzymes only augments both the biphasic H2O2 level and caspase‐dependent apoptosis induced by TNF‐α in HeLa cervical cancer cell line, but they did not modulate necrotic cell death. Although the depletion of any of the endogenous antioxidant enzymes results in global increase of the intracellular ROS level generated in response to TNF‐α‐induced apoptosis, PrxII regulatable H2O2 only influences caspase 8‐dependent apoptosis. Moreover, GPx I have a dominant effect on stress kinase activation and consequential cell death including p38 and JNK. Collectively, these results suggest that a novel mechanism underlying the selective action of intracellular ROS, precisely H2O2, in TNF α‐induced apoptosis. This study was supported by a grant of Discovery and validation of new drug project (2011‐0030195).