Cell detachment and apoptosis induction of immortalized human prostate epithelial cells are associated with early accumulation of a 45 kDa nuclear isoform of clusterin

Caccamo, Alessandro E.; Scaltriti, Maurizio; Caporali, Andrea; D’Arca, Domenico; Scorcioni, Francesca; Astancolle, Serenella; Mangiola, Massimo; Bettuzzi, Saverio

doi:10.1042/bj20040158

Cited by 56 publications

(63 citation statements)

References 54 publications

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“…In contrast, Trougakos et al (16,29) reported that in osteosarcoma cells either clu overexpression or clu knockdown could result in apoptosis of these cells. Furthermore, it recently became evident that numbers of clu functions were related to intracellular forms of the protein, in particular for apoptosis (30). Lastly, it has been demonstrated that overexpression of intracellular CLU caused clonogenic toxicity in PC-3 androgen-independent prostate cancer cells (31).…”

Section: Discussionmentioning

confidence: 99%

Characterization and Functional Consequences of Underexpression of Clusterin in Rheumatoid Arthritis

Devauchelle

Essabbani

Pinieux

et al. 2006

The Journal of Immunology

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We previously compared by microarray analysis gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) tissues. Among the set of genes identified as a molecular signature of RA, clusterin (clu) was one of the most differentially expressed. In the present study we sought to assess the expression and the role of CLU (mRNA and protein) in the affected joints and in cultured fibroblast-like synoviocytes (FLS) and to determine its functional role. Quantitative RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, and Western blot were used to specify and quantify the expression of CLU in ex vivo synovial tissue. In synovial tissue, the protein was predominantly expressed by synoviocytes and it was detected in synovial fluids. Both full-length and spliced isoform CLU mRNA levels of expression were lower in RA tissues compared with OA and healthy synovium. In synovium and in cultured FLS, the overexpression of CLU concerned all protein isoforms in OA whereas in RA, the intracellular forms of the protein were barely detectable. Transgenic overexpression of CLU in RA FLS promoted apoptosis within 24 h. We observed that CLU knockdown with small interfering RNA promoted IL-6 and IL-8 production. CLU interacted with phosphorylated IκBα. Differential expression of CLU by OA and RA FLS appeared to be an intrinsic property of the cells. Expression of intracellular isoforms of CLU is differentially regulated between OA and RA. We propose that in RA joints, high levels of extracellular CLU and low expression of intracellular CLU may enhance NF-κB activation and survival of the synoviocytes.

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Section: Discussionmentioning

confidence: 99%

Characterization and Functional Consequences of Underexpression of Clusterin in Rheumatoid Arthritis

Devauchelle

Essabbani

Pinieux

et al. 2006

The Journal of Immunology

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“…Antisense oligonucleotides and small interfering RNAs (siRNA) targeting the full-length CLU have been reported to induce apoptosis and chemosensitivity in vitro in prostate cancer xenografts (26)(27)(28)(29) and in prostate cancer patients (30,31). On the other hand, nCLU accumulation has been observed in dying prostate cells challenged with proapoptotic stimuli (4,5,17). Overexpression of nCLU has been reported to induce G 2 -M phase arrest and caspase-dependent apoptosis in prostate cancer cells (6).…”

Section: Introductionmentioning

confidence: 99%

“…CLU is considered an enigmatic protein because of the difficulties in the definition of its precise functions; at the moment, an important debate concerns its implication in carcinogenesis, particularly in prostate cancer development. On this issue, the data currently available are controversial because CLU has been suggested as being either a proapoptotic or a prosurvival factor (3)(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

et al. 2007

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Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with ''full-length'' CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to A-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and A-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to A-actinin. [Cancer Res 2007; 67(21):10325-33]

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“…Such observations were consistent with the reports that accumulation of an intracellular nCLU isoform is associated with anoikis induction in PNT1A cells. 25 Transient nCLU overexpression triggered cell death in SKOV3 cells…”

Section: Subcellular Localization Of Clu Isforms In Skov3 Cells and Tmentioning

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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Cell detachment and apoptosis induction of immortalized human prostate epithelial cells are associated with early accumulation of a 45 kDa nuclear isoform of clusterin

Cited by 56 publications

References 54 publications

Characterization and Functional Consequences of Underexpression of Clusterin in Rheumatoid Arthritis

Characterization and Functional Consequences of Underexpression of Clusterin in Rheumatoid Arthritis

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

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

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