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J. Biol. Chem., Vol. 283, Issue 13, 8423-8433, March 28, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/13/8423    most recent M707687200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wan, K. F. Articles by Yu, V. C. PubMed PubMed Citation Articles by Wan, K. F. Articles by Yu, V. C. Social Bookmarking                      What's this?

Chelerythrine Induces Apoptosis through a Bax/Bak-independent Mitochondrial Mechanism^*

Kah Fei Wan, Shing-Leng Chan, Sunil Kumar Sukumaran, Mei-Chin Lee, and Victor C. Yu, An adjunct staff of the Dept. of Pharmacology, National University of Singapore¹

From the Institute of Molecular and Cell Biology, A^*STAR (Agency for Science, Technology, and Research), 61 Biopolis Dr. (Proteos), Singapore 138673 and Oncology Research Institute, National University of Singapore, 28 Medical Dr., Centre For Life Sciences, Cancer Program, Singapore 117456

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 (_m) 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.

Received for publication, September 13, 2007 , and in revised form, December 17, 2007.

^* This work was supported by the Biomedical Research Council of A^*STAR (Agency for Science, Technology, and Research), Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ To whom correspondence should be addressed. Tel.: 65-65869672; Fax: 65-67791117; E-mail: mcbyuck{at}imcb.a-star.edu.sg.

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