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Chelerythrine induces apoptosis through a Bax/Bak-independent mitochondrial mechanism
- Source :
- The Journal of biological chemistry. 283(13)
- Publication Year :
- 2008
-
Abstract
- Although murine embryonic fibroblasts (MEFs) with Bax or Bak deleted displayed no defect in apoptosis signaling, MEFs with Bax and Bak double knock-out (DKO) showed dramatic resistance to diverse apoptotic stimuli, suggesting that Bax and Bak are redundant but essential regulators for apoptosis signaling. Chelerythrine has recently been identified as a Bcl-xL inhibitor that is capable of triggering apoptosis via direct action on mitochondria. Here we report that in contrast to classic apoptotic stimuli, chelerythrine is fully competent in inducing apoptosis in the DKO MEFs. Wild-type and DKO MEFs are equally sensitive to chelerythrine-induced morphological and biochemical changes associated with apoptosis phenotype. Interestingly, chelerythrine-mediated release of cytochrome c is rapid and precedes Bax translocation and integration. Although the BH3 peptide of Bim is totally inactive in releasing cytochrome c from isolated mitochondria of DKO MEFs, chelerythrine maintains its potency and efficacy in inducing direct release of cytochrome c from these mitochondria. Furthermore, chelerythrine-mediated mitochondrial swelling and loss in mitochondrial membrane potential (ΔΨm) are inhibited by cyclosporine A, suggesting that mitochondrial permeability transition pore is involved in chelerythrine-induced apoptosis. Although certain apoptotic stimuli have been shown to elicit cytotoxic effect in the DKO MEFs through alternate death mechanisms, chelerythrine does not appear to engage necrotic or autophagic death mechanism to trigger cell death in the DKO MEFs. These results, thus, argue for the existence of an alternative Bax/Bak-independent apoptotic mechanism that involves cyclosporine A-sensitive mitochondrial membrane permeability.
- Subjects :
- Programmed cell death
Apoptosis
Biochemistry
Mitochondrial apoptosis-induced channel
Sensitivity and Specificity
chemistry.chemical_compound
Mice
Bcl-2-associated X protein
Animals
Inner mitochondrial membrane
Molecular Biology
Cells, Cultured
bcl-2-Associated X Protein
Benzophenanthridines
Membrane Potential, Mitochondrial
biology
Cytochrome c
Mechanisms of Signal Transduction
Cytochromes c
Cell Biology
Molecular biology
Cell biology
Mitochondria
Enzyme Activation
Chelerythrine
bcl-2 Homologous Antagonist-Killer Protein
chemistry
Mitochondrial permeability transition pore
Caspases
biology.protein
Cyclosporine
Bcl-2 Homologous Antagonist-Killer Protein
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 283
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....fb20c80d45b16a1ed53972c92d7652d4