| The augmentation of TNFalpha-induced cell death in murine L929 fibrosarcoma by the pan-caspase inhibitor Z-VAD-fmk through pre-mitochondrial and MAPK-dependent pathways. | |
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MedLine Citation:
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PMID: 16418768 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We investigated the mechanism of the pan-caspase inhibitor z-VAD-fmk's augmentation of TNFalpha-induced L929 cell death and found this mechanism differs from that of TNFalpha-induced L929 cell death. In the presence of 20 ng/ml TNFalpha, z-VAD-fmk initiated apoptosis and necrosis in the majority of L929 cells as measured by an agarose gel electrophoresis and lactate dehydrogenase(LDH)activity based assay. Mitochondrial permeability transition (MPT) inhibitor (cyclosporine A) effectively inhibited z-VAD-fmk-augmented cell death. In addition, z-VAD-fmk plus TNFalpha increased Bax expression without affecting Bcl-2 and cytochrome expression. Western-blot analysis showed that z-VAD-fmk plus TNFalpha caused persistent JNK activation and ERK inactivation. Poly(ADP-ribose) polymerase (PARP) inhibitor (DPQ) effectively reversed the cell death which was augmented by z-VAD-fmk, and z-VAD-fmk plus TNFalpha also caused PARP cleavage to an 85 KDa fragment. These results indicate that in the presence of TNFalpha, z-VAD-fmk further augments cell death which requires the mitochondrial permeability transition and the JNK activation. However, we did not detect the changes in cytochrome c expression and the participation of caspase-9 in this process, suggesting that there might exist an unknown signal pathway(s) from the mitochondria to the downstream protein PARP, which is cleaved in a caspase-independent manner. |
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Authors:
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Jian Huang; Lijun Wu; Shin-Ichi Tashiro; Satoshi Onodera; Takashi Ikejima |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Acta medica Okayama Volume: 59 ISSN: 0386-300X ISO Abbreviation: Acta Med. Okayama Publication Date: 2005 Dec |
Date Detail:
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Created Date: 2006-01-18 Completed Date: 2006-02-09 Revised Date: 2006-04-13 |
Medline Journal Info:
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Nlm Unique ID: 0417611 Medline TA: Acta Med Okayama Country: Japan |
Other Details:
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Languages: eng Pagination: 253-60 Citation Subset: IM |
Affiliation:
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China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, PR China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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pharmacology* Animals Apoptosis / drug effects* Caspases / physiology Cell Line, Tumor Fibrosarcoma / pathology* MAP Kinase Signaling System / physiology* Mice Mitochondria / physiology* Necrosis Poly(ADP-ribose) Polymerases / physiology Signal Transduction Tumor Necrosis Factor-alpha / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Chloromethyl Ketones; 0/Tumor Necrosis Factor-alpha; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspases |
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