Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression

Bettuzzi, Saverio; Scorcioni, Francesca; Astancolle, Serenella; Davalli, Pierpaola; Scaltriti, Maurizio; Corti, Angelo

doi:10.1038/sj.onc.1205594

Cited by 78 publications

(96 citation statements)

References 41 publications

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“…8,38 In fact, not many studies showed a decrease in sCLU in tumours like that of a proapoptotic. A few reports do, however, suggest decreased sCLU levels in specific cancers, including nonmelanoma skin cancer, 40 oesophageal squamous cell carcinoma, 41 neuroblastoma, 22 prostate, 11,37 and pancreatic cancer 42 (Table 1). In one study, CLU expression was analysed during progression of prostate cancer.…”

Section: Expression Of Clu In Malignant Tumours and Its Potential Rolmentioning

confidence: 99%

“…Furthermore, sCLU confers resistance by some unknown mechanism when overexpressed. 9 The novel therapeutic strategy of silencing sCLU expression to overcome resistance to cancer therapy is of interest for the treatment of cancers that overexpress sCLU as in kidney, 40 k Protein Pancreatic cancer 41 k mRNA Prostate cancer 11,37 k mRNA m * : Increase in expression; k ** : decrease in expression Clusterin in human cancers B Shannan et al prostate, 44 colon, breast, and lung tumours 14 (Table 2). Recent findings support the concept that silencing sCLU expression can enhance the cytotoxicity of various chemotherapeutic agents 1,49 as well as IR.…”

Section: Clu As a Therapeutic Target In Malignanciesmentioning

confidence: 99%

“…Early studies seemed to establish that CLU gene expression was a marker of apoptotic cell loss. 5 Importantly, CLU upregulation has been reported in various human malignancies, including bladder, 6 kidney, 7 prostate, [8][9][10][11] colon, 3 breast, 12,13 and lung 14 tumours.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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Clusterin (CLU) has been implicated in various cell functions involved in carcinogenesis and tumour progression. There are two known CLU protein isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is proapoptotic, and a secretory form (sCLU) is prosurvival. CLU expression has been associated with tumorigenesis of various malignancies, including tumours of prostate, colon, and breast. Furthermore, CLU expression is modulated by many factors that are believed to regulate tumour growth and/or apoptosis, including 1,25-dihydroxyvitamin D 3 , transforming growth factor beta-1, ultraviolet radiation, and IR. sCLU upregulation appears to be a general molecular stress response. Presently, preliminary results indicate that therapeutic modalities targeting CLU may be effective in cancer treatment. However, such strategies should make sure that nCLU is not eliminated or reduced. This review summarizes our present understanding of the importance of CLU in various physiological functions including tumour growth, and discusses its relevance to future cancer therapy.

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Section: Expression Of Clu In Malignant Tumours and Its Potential Rolmentioning

confidence: 99%

Section: Clu As a Therapeutic Target In Malignanciesmentioning

confidence: 99%

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

et al. 2005

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“…20 We have previously reported that CLU overexpression inhibits cell cycle progression of simian virus 40(SV40)-immortalized human prostate PNT2 and PNT1A epithelial cells. 21 To further assess the role of CLU in apoptotic processes we have studied its expression pattern during the regulation of calcium homeostasis. Ca 2 þ is an important regulator of apoptosis and cell survival.…”

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confidence: 99%

“…FACS analysis of cell cycle progression was performed as previously described. 21 Values are the mean of cell population (% of total)7S.D. (n ¼ 5).…”

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Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

et al. 2004

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Clusterin (CLU) is a secreted heterodimeric glycoprotein thatcan be produced almost ubiquitously in mammalians tissues.1Its gene expression is subjected to complex regulation and canchange enormously according to different stimuli.2 Cloned andidentified as the most potently induced gene in the regressingrat ventral prostate following androgen-ablation,3 CLU wasalmost simultaneously characterized and isolated by differentresearch groups working in widely divergent areas.2 CLU iscoded by a single copy gene, located on chromosome 8.4 Thegene codes for an initial precursor peptide glycosylated andcleaved into two a and b chains of 40 kDa each, held togetherby a unique five disulfide bond motif in the extracellular matureform.1 This secreted form of CLU has been suggested to act asa molecular chaperone following stress-induced injury,5clearing extracellular debris.6 However, it has been reportedthe existence of an inactive, cytoplasmic form of CLUproduced by alternative splicing that is converted by ionizingirradiation to a truncated mature nuclear isoform,7 which bindsthe Ku70/Ku80 complex in cell-free systems8 inhibiting cellgrowth and survival7 probably by a caspase-3-independentmechanism.9 Other alternative CLU isoforms, produced eitherby exon skipping10 or by post-translational modificationsactivated by apoptosis,11,12 were recently described. Thesedifferent isoforms of CLU have been suggested to beantiapoptotic6,13 or proapoptotic.7,10,12,14–16These controversial reports on the role of CLU might berelated to specific proteomic profiles that are produced bydifferent apoptotic stimuli (i.e. the general protein pattern ofCLU and the relative ratio between different CLU isoforms).This might explain why CLU has been involved in a plethora ofpathophysiological processes, including cell–cell and cell–matrix adhesion, cell differentiation, transformation, aging17,18and cancer,19 but its biological role still remains to be clearlyestablished. Reports suggesting that CLU may be a potentialtumor suppressor gene include the finding that CLU suppressesNF-kB activity and the metastatic phenotype ofneuroblastoma cells.20 We have previously reported that CLUoverexpression inhibits cell cycle progression of simian virus40(SV40)-immortalized human prostate PNT2 and PNT1Aepithelial cells.21To further assess the role of CLU in apoptotic processes wehave studied its expression pattern during the regulation ofcalcium homeostasis. Ca2þ is an important regulator ofapoptosis and cell survival.22,23,24 Both pathological increaseof Ca2þ concentration in the cytosol compartment byinophores25 and depletion of intracellular Ca2þ stores maytrigger apoptosis by disrupting intracellular architecture andallowing effectors to gain access to their substrates.24,26,27Activation of apoptotic endonucleases28 eliciting DNA cleavageand chromatin condensation has beenwell documented.29,30,31A tight buffering of intracellular Ca2þ is required for normalgrowth. In fact, apoptosis can be induced by Ca2þ mobilizationfrom intracellular pools,23,24,27 chelati...

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Clusterin (SGP‐2, ApoJ) expression is downregulated in low‐ and high‐grade human prostate cancer

Scaltriti

Brausi

Amorosi

et al. 2003

Intl Journal of Cancer

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Clusterin is overexpressed during tissue and cell involution and downregulated in proliferating cells. Its role in cell survival, cell death and neoplastic transformation remains debated. We studied the expression and distribution of clusterin mRNA and protein in human prostate carcinoma (CaP) specimens of different degrees of malignancy. Fresh CaP specimens were obtained from 25 patients subjected to longterm androgen ablation before surgery. Clusterin expression was studied by Northern and Western analysis, in situ hybridization and immunohistochemistry, in comparison with Gas1 and histone H3 mRNA (markers of cell quiescence and S phase of the cell cycle, respectively). Clusterin is downregulated in CaP in comparison with matched benign controls. In low-grade CaP, clusterin colocalized with Gas1 to the stromal compartment, and in some glands, the basal lamina was heavily stained. In high-grade CaP clusterin stained the remnants of stromal matrix while histone H3 localized to cancer cells, which were very rarely clusterin positive. High clusterin expression was found in the branches of a nerve infiltrated by tumor. The periglandular clusterin expression found in lowgrade CaP could result from induction of quiescence and/or apoptosis of prostatic fibroblasts lining those glands in which tumor invasion is at an initial stage, involving basal lamina. In advanced CaP, the staining of the remnants of the extracellular matrix suggests a role for clusterin in the process of dismantling the stromal organization caused by cancer progression.

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Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression

Cited by 78 publications

References 41 publications

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

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

Ca2+ depletion induces nuclear clusterin, a novel effector of apoptosis in immortalized human prostate cells

Clusterin (SGP‐2, ApoJ) expression is downregulated in low‐ and high‐grade human prostate cancer

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