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Clusterin inhibits apoptosis by interacting with activated Bax

Nature Cell Biology volume 7, pages 909–915 (2005)Cite this article

Abstract

Clusterin is an enigmatic glycoprotein that is overexpressed in several human cancers such as prostate and breast cancers, and squamous cell carcinoma1,2. Because the suppression of clusterin expression renders human cancer cells sensitive to chemotherapeutic drug-mediated apoptosis, it is currently an antisense target in clinical trials for prostate cancer. However, the molecular mechanisms by which clusterin inhibits apoptosis in human cancer cells are unknown. Here we report that intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria. Intriguingly, in contrast to other inhibitors of Bax, clusterin specifically interacts with conformation-altered Bax in response to chemotherapeutic drugs. This interaction impedes Bax oligomerization, which leads to the release of cytochrome c from mitochondria and caspase activation. Moreover, we also find that clusterin inhibits oncogenic c-Myc-mediated apoptosis by interacting with conformation-altered Bax. Clusterin promotes c-Myc-mediated transformation in vitro and tumour progression in vivo. Taken together, our results suggest that the elevated level of clusterin in human cancers may promote oncogenic transformation and tumour progression by interfering with Bax pro-apoptotic activities.

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Figure 1: Clusterin inhibits apoptosis in HT1080 cells.
Figure 2: Clusterin interacts with conformation-altered Bax and inhibits its oligomerization in HT1080 cells.
Figure 3: Clusterin inhibits c-Myc-mediated apoptosis by interacting with conformation-altered Bax.
Figure 4: Clusterin cooperates with c-Myc in oncogenic transformation in vitro and in tumour formation and progression in vivo.
Figure 5: The elevated endogenous clusterin interacted with conformation-altered Bax and inhibited apoptosis in prostate cancer cells.

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Acknowledgements

We thank Z. You for technical help, A. S. Baldwin for critically reading the manuscript and E. White for inspiring discussion. This study was supported by National Institutes of Health and the US Army Research Office (DAAD19-03-1-0168).

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Authors and Affiliations

  1. Department of Biological and Materials Sciences, Laboratory of Molecular Signaling and Apoptosis, School of Dentistry, University of Michigan, Ann Arbor, 48109-1078, MI, USA

    Honglai Zhang, Jin Koo Kim & Cun-Yu Wang

  2. Department of Cell and Developmental Biology, Microscopy and Image-Analysis Core, School of Dentistry, University of Michigan, Ann Arbor, 48109-1078, MI, USA

    Chris A. Edwards

  3. Life Science Institute, School of Dentistry, University of Michigan, Ann Arbor, 48109-1078, MI, USA

    Zhaohui Xu

  4. Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, 48109-1078, MI, USA

    Russell Taichman

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  1. Honglai Zhang
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Correspondence to Cun-Yu Wang.

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Zhang, H., Kim, J., Edwards, C. et al. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol 7, 909–915 (2005). https://doi.org/10.1038/ncb1291

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