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Clusterin inhibits apoptosis by interacting with activated Bax
Abstract
Clusterin is an enigmatic glycoprotein that is overexpressed in several human cancers such as prostate and breast cancers, and squamous cell carcinoma. 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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“CLU gene encodes clusterin or APOJ that besides its functions in lipid transport, membrane recycling, cell adhesion, and apoptosis (90, 444, 600, 677) affects transvascular A 𝛃 clearance by promoting A 𝛃 42 efflux across the BBB (580).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [677]
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Blood-Brain Barrier: From Physiology to Disease and Back
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Mechanisms of resistance in castration-resistant prostate cancer (CRPC).
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Metadata
- Authors
- Zhang, H., Kim, J. K., Edwards, C. A., Xu, Z., Taichman, R., & Wang, C.-Y.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Cun-Yu
- Venue
- Nature Cell Biology
- Published
- 2005-08-21
- Volume
- 7
- Issue
- 9
- Pages
- 909-915
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2093107372
- Cited by
- 453
- References
- 27
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 13 · 2023: 18 · 2022: 19 · 2021: 22 · 2020: 21 · 2019: 16 · 2018: 19 · 2017: 16 · 2016: 18 · 2015: 20 · 2014: 24 · 2013: 27 · 2012: 31
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Army Research Office
- Topics
- Health Sciences › Medicine › Oncology › Clusterin in disease pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Keywords
- clusterin, apoptosis inhibition, Bax activation, Bax oligomerization, cytochrome c release, caspase activation, c-Myc, oncogenic transformation, tumor progression, chemosensitization, prostate cancer, breast cancer, squamous cell carcinoma, mitochondrial apoptosis
- MeSH terms
- Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Glycoproteins, Humans, Mitochondria, Neoplasms, Protein Conformation, Proto-Oncogene Proteins c-myc, Apoptosis, Molecular Chaperones, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Caspases, Cytochromes c, Cell Line, Tumor, bcl-2-Associated X Protein, Clusterin, Rats
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