Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

Shannan, Batool; Seifert, Markus; Leskov, Konstantin; Willis, Joseph E.; Boothman, David A.; Tilgen, Wolfgang; Reichrath, Joerg

doi:10.1038/sj.cdd.4401779

Cited by 287 publications

(292 citation statements)

References 50 publications

(124 reference statements)

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“…23,24 The precise physiological role of clusterin is unknown, although a large diversity of functions has been suggested. 25 In particular, it has been shown that the chaperone behavior of clusterin can be observed in vitro and appears similar to that described for the small heat shock proteins. 26,27 Clusterin has been reported to inhibit in vitro fibril formation by a number of proteins and peptides linked to aggregation diseases including the Aβ peptide, apo C-II, and the prion neuropeptide 106-126.…”

Section: Introductionmentioning

confidence: 83%

The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation by Interacting with Prefibrillar Species

Kumita

Poon

Caddy

et al. 2007

Journal of Molecular Biology

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We have studied the effects of the extracellular molecular chaperone, clusterin, on the in vitro aggregation of mutational variants of human lysozyme, including one associated with familial amyloid disease. The aggregation of the amyloidogenic variant I56T is inhibited significantly at clusterin to lysozyme ratios as low as 1:80 (i.e. one clusterin molecule per 80 lysozyme molecules). Experiments indicate that under the conditions where inhibition of aggregation occurs, clusterin does not bind detectably to the native or fibrillar states of lysozyme, or to the monomeric transient intermediate known to be a key species in the aggregation reaction. Rather, it seems to interact with oligomeric species that are present at low concentrations during the lag (nucleation) phase of the aggregation reaction. This behavior suggests that clusterin, and perhaps other extracellular chaperones, could have a key role in curtailing the potentially pathogenic effects of the misfolding and aggregation of proteins that, like lysozyme, are secreted into the extracellular environment.

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Section: Introductionmentioning

confidence: 83%

The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation by Interacting with Prefibrillar Species

Kumita

Poon

Caddy

et al. 2007

Journal of Molecular Biology

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“…Furthermore, it has been proposed to be a potential diagnostic and prognostic marker for colon carcinoma aggressiveness. 66 WFDC2 is known to be overexpressed in a number of cell lines, including ovarian, renal, lung, colon, and breast. The bulk of initial studies on WFDC2 were focused on using it as a biomarker for ovarian carcinoma.…”

Section: Identification Of Proteins Known To Be Associated With Cancersmentioning

confidence: 99%

Identification of Candidate Biomarker Proteins Released by Human Endometrial and Cervical Cancer Cells Using Two-Dimensional Liquid Chromatography/Tandem Mass Spectrometry

DeSouza

Ghanny

et al. 2007

J. Proteome Res.

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“…3 It is encoded by a single-copy gene located on chromosome 8p21-p12. However, CLU expression is complex, appearing as different forms in different cell compartments.…”

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confidence: 99%

Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer

Xue

Wang

et al. 2009

Intl Journal of Cancer

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Clusterin (CLU) is a multivalent glycoprotein with ubiquitous tissue distribution. To address the possible differential functional roles assumed by different isoforms of CLU in the progression of human ovarian cancer, we constructed 2 human ovarian cancer cell models that represent examples of contradistinctive CLU expression levels. One is constitutively overexpressing different clusterin isoforms in SKOV3 cells by transfection of the 3 different expression vectors, another is silencing the intrinsically expressing clusterin in cisplatin-resistant human A2780-cis(CP70) tumor cells with the usage of shRNA-mediated CLU gene silencing. Then, the different cellular localization, biological effects, and functional roles played in tumor progression and drug resistances were studied. We found that (i) in the distinct cellular contexts of human ovarian carcinoma SKOV3 and CP70 cells assayed, sCLU is a central molecule in cell homeostasis that functions as a cytoprotective protein, whereas nCLU is proapoptotic; (ii) In SKOV3 cells, nuclear localization of the truncated CLU is NLS dependent, without which the pnCLU protein was sequestrated in cytoplasm to prevent cytotoxicity. (iii) sCLU plays a significant role in the development of the chemoresistance phenotype in ovarian cancer cells. Moreover, with the CLU-specific shRNA oligonucleotides, we successfully sensitized cells for chemotherapy, and inhibited cells' proliferation, migration and invasion. Collectively, our results reveal that, CLU gene expression might play a crucial role in ovarian cancer progression, adaptation and eventual resistance to chemotherapy through differential processing of CLU isoforms. Specifically, sCLU as an antiapoptotic protein, upregulated in an adaptive cell-survival manner by chemotherapy, confers resistance to various cell-death triggers. ' UICCKey words: clusterin; ovarian carcinoma; RNAi; chemoresistance; metastasis Ovarian cancer, the leading cause of death from gynecological malignancy, is the seventh most common malignancy in women worldwide and is the fourth leading cause of death from malignant disease among American women. In more than two thirds of the cases, patients show widespread metastatic dissemination at time of the initial presentation. 1 Because of advances in surgical management and chemotherapeutic options over the last 3 decades, the median survival rate for ovarian cancer patients has improved. Nevertheless, overall survival has not significantly changed. Cisplatin-based combination chemotherapy is initially an effective mechanism to arrest malignancy. However, after preliminary success in tumor regression, recurrence and resistance to further chemotherapeutic treatment often ensues. This amplification in drug resistance has also been correlated with the development of a broad cross-resistance in ovarian cancer to other unrelated chemotherapeutic compounds. 2 Therefore, shortages of suitable biologic markers, and limitations in the timely screening methods, early metastasis and resistance to anticancer chemother...

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Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer

Cited by 287 publications

References 50 publications

The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation by Interacting with Prefibrillar Species

The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation by Interacting with Prefibrillar Species

Identification of Candidate Biomarker Proteins Released by Human Endometrial and Cervical Cancer Cells Using Two-Dimensional Liquid Chromatography/Tandem Mass Spectrometry

Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer

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