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Cited by 160Clusterin in disease pathologyCell death mechanisms and regulationHeat shock proteins research

Intracellular Clusterin Inhibits Mitochondrial Apoptosis by Suppressing p53-Activating Stress Signals and Stabilizing the Cytosolic Ku70-Bax Protein Complex

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Trougakos, Ioannis P., Lourda, Magda, Antonelou, Marianna H., Kletsas, Dimitris, Gorgoulis, Vassilis G., Papassideri, Issidora S., Zou, Yonglong, Margaritis, Lukas H. +2 more·2009·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-08-1805PMC PMC4483278

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Abstract

Purpose: Secretory clusterin (sCLU)/apolipoprotein J is an extracellular chaperone that has been functionally implicated in DNA repair, cell cycle regulation, apoptotic cell death, and tumorigenesis. It exerts a prosurvival function against most therapeutic treatments for cancer and is currently an antisense target in clinical trials for tumor therapy. However, the molecular mechanisms underlying its function remained largely unknown. Experimental Design: The molecular effects of small interfering RNA-mediated sCLU depletion in nonstressed human cancer cells were examined by focusing entirely on the endogenously expressed sCLU protein molecules and combining molecular, biochemical, and microscopic approaches. Results: We report here that sCLU depletion in nonstressed human cancer cells signals stress that induces p53-dependent growth retardation and high rates of endogenous apoptosis. We discovered that increased apoptosis in sCLU-depleted cells correlates to altered ratios of proapoptotic to antiapoptotic Bcl-2 protein family members, is amplified by p53, and is executed by mitochondrial dysfunction. sCLU depletion-related stress signals originate from several sites, because sCLU is an integral component of not only the secretory pathway but also the nucleocytosolic continuum and mitochondria. In the cytoplasm, sCLU depletion disrupts the Ku70-Bax complex and triggers Bax activation and relocation to mitochondria. We show that sCLU binds and thereby stabilizes the Ku70-Bax protein complex serving as a cytosol retention factor for Bax. Conclusions: We suggest that elevated sCLU levels may enhance tumorigenesis by interfering with Bax proapoptotic activities and contribute to one of the major characteristics of cancer cells, that is, resistance to apoptosis.

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  • CLU gene encodes clusterin or APOJ that besides its functions in lipid transport, membrane recycling, cell adhesion, and apoptosis affects transvascular Aβ clearance by promoting Aβ42 efflux across the BBB.

    “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 [600]

    The paper’s introductory passage identifies clusterin as apolipoprotein J and the predominant product of the human CLU gene; the Purpose and Conclusions passages discuss its role in apoptosis (pages not provided). The cited portion of the sentence also lists lipid transport, membrane recycling, and cell adhesion, which these passages and searches of the full-text copy do not support. The separate claim about Aβ42 efflux across the BBB is attached to citation 580, not this source. (LLM, conf=0.88)

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Research works printed but not linked: 37

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Authors
Trougakos, I. P., Lourda, M., Antonelou, M. H., Kletsas, D., Gorgoulis, V. G., Papassideri, I. S., Zou, Y., Margaritis, L. H., Boothman, D. A., & Gonos, E. S.
Affiliations
  • National Hellenic Research Foundation (GR)
  • 2Department of Cell Biology and Biophysics, Faculty of Biology, and
  • National Centre of Scientific Research "Demokritos" (GR)
  • National and Kapodistrian University of Athens (GR)
  • The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2008-12-31
Volume
15
Issue
1
Pages
48-59
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-08-1805
PMC
PMC4483278
OpenAlex
W2114186198
Cited by
160
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 11 · 2021: 13 · 2020: 15 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 7 · 2015: 7 · 2014: 12 · 2013: 15 · 2012: 11
FWCI
5.45
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • National Hellenic Research Foundation Helios Repository (National Hellenic Research Foundation) (submittedVersion)
Funders
  • Εθνικό 'Ίδρυμα Ερευνών
  • University of Ioannina
  • Beatson Institute for Cancer Research
  • National Cancer Institute (R01CA078530, P50CA070907, P30CA142543)
  • National Institute of Neurological Disorders and Stroke
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
secretory clusterin, clusterin, apoptosis, mitochondrial apoptosis, p53, Bax activation, Bcl-2 family proteins, mitochondrial dysfunction, stress signals, tumor cell survival, antisense therapy
MeSH terms
Ku Autoantigen, Cytosol, DNA-Binding Proteins, Humans, Mitochondria, Organelles, Genes, p53, RNA, Small Interfering, Antigens, Nuclear, Cell Line, Tumor, bcl-2-Associated X Protein, Clusterin

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