| 18705696 |
Liu WH, Chang LS: Reactive oxygen species and p38 mitogen-activated protein kinase induce apoptotic death of U937 cells in response to Naja nigricollis toxin gamma. J Cell Mol Med. 2008 Aug 14.
The aim of the present study is to elucidate the signaling components related to Naja nigricollis toxin gamma-induced apoptosis in human leukemia U937 cells. It was found that toxin gamma-induced apoptotic cell death was attributed mainly to activation of p38 MAPK, ROS generation and loss of mitochondrial membrane potential (DeltaPsim). Subsequent modulation of Bcl-2 family member and cytochrome c release accompanied with activation of caspase-9 and -3 were involved in the death of U937 cells. SB202190 (p38 MAPK inhibitor) and N-acetylcysteine (antioxidant) attenuated significantly toxin gamma-induced cell death and loss of DeltaPsim, and abolished completely the production of ROS. In contrast to N-acetylcysteine, degradation of Bcl-2/Bcl-X (L) and mitochondrial localization of Bax were notably decreased by SB202190. Inhibitors of electron transport (rotenone and antimycin A) or inhibitor of mitochondrial permeability transition pore (cyclosporine A) reduced the effect of toxin gamma on ROS generation, loss of DeltaPsim and cytochrome c release. Noticeably, pretreatment with N-acetylcysteine or rotenone eliminated markedly ROS accompanied with reduction in p38 MAPK activation. Taken together, these results suggest that the cytotoxicity of toxin gamma is initiated by p38 MAPK-mediated mitochondrial dysfunction followed by ROS production and activation of caspases, and that ROS further augments p38 MAPK activation and mitochondrial alteration. |
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