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Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells

Oncogene volume 22, pages 2643–2654 (2003)Cite this article

Abstract

Chemotherapy resistance remains a major clinical problem in patients with B-cell chronic lymphocytic leukemia (B-CLL). Proteasome inhibitors are able to induce apoptosis in chemotherapy-resistant B-CLL cells in vitro. Exposure of B-CLL cells to the proteasome inhibitors, MG132 and lactacystin, resulted in inhibition of proteasomal activity within 30 min of treatment and was accompanied by an increase in the level of ubiquitinated proteins. Proteasome inhibitors did not alter the levels of expression of the proapoptotic Bcl-2 family proteins, Bax and Bid, prior to the onset of apoptosis. Instead, proteasome inhibitors induced a caspase-independent conformational change in Bax (as shown by a conformation-specific Bax antibody) and its translocation to mitochondria, resulting in mitochondrial perturbation, as evidenced by loss of the mitochondrial membrane potential and cytochrome c release. Similar conformational change and subcellular localization of Bax were observed during apoptosis induced with fludarabine, chlorambucil and prednisolone. These data suggest that alteration of Bax conformation and its redistribution to mitochondria are common and early features of B-CLL apoptosis in response to proteasome inhibitors and other chemotherapeutic agents.

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Acknowledgements

We thank Dr Marion MacFarlane, Dr Shawn Bratton, and Prof. Pierluigi Nicotera for their advice and critique of the manuscript. We thank Kul Sikand for his invaluable assistance with the confocal analysis. This work was supported in part by the Medical Research Council and a grant from the European Union (Grant # QLG1-1999-00739).

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  1. Grant Dewson and Roger T Snowden: Authors contributed equally to the work

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  1. MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester, LE1 9HN, UK

    Grant Dewson, Roger T Snowden, Jason B Almond, Martin J S Dyer & Gerald M Cohen

  2. Department of Hematology, Robert Kilpatrick Clinical Sciences Building, PO Box 65, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK

    Martin J S Dyer

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  1. Grant Dewson
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Correspondence to Gerald M Cohen.

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Dewson, G., Snowden, R., Almond, J. et al. Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. Oncogene 22, 2643–2654 (2003). https://doi.org/10.1038/sj.onc.1206326

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