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PubMed1999

Subcellular distribution, secretion, and posttranslational modifications of clusterin in thyrocytes.

A prominent secretory glycoprotein was detected in the culture medium of porcine thyrocytes which was identified as clusterin by microsequencing. Treatment of thyrocytes with thyroid stimulating hormone revealed a tight regulation of both synthesis and secretion of clusterin, with a distinct fraction of clusterin being always associated with the cells. At least three N-bound glycans were found on each subunit of clusterin, receiving most of the incorporated [(32)P]phosphate-label. Binding of clusterin to the immobilized cation-independent mannose 6-phosphate (M6P) receptor indicated that part of the phosphate label was contained in M6P moieties. Immunolabeling of cultured thyrocytes and of thyrocytes in situ showed clusterin on the apical cell surfaces where it colocalized with gp330/megalin, which is known to serve as a binding site for clusterin. The association with the apical plasma membrane, which, in thyrocytes, carries the iodinating system, was confirmed by biosynthetic iodination, an as yet unknown posttranslational modification of clusterin. On the basolateral plasma membranes clusterin was found within distinct, bipartite patches, suggesting that it is a constituent of cell-adhesion complexes and that it participates in cell-cell and cell-matrix interactions.

Amidohydrolases↗
PubMed2002

Urinary clusterin levels in the rat correlate with the severity of tubular damage and may help to differentiate between glomerular and tubular injuries.

Clusterin is a secreted glycoprotein that is synthesized after several types of tubular injury. We therefore wondered whether the urinary excretion of clusterin could serve as a parameter to determine the severity of tubular damage. Using an affinity-purified rabbit antiserum raised against recombinant clusterin, we established an enzyme-linked immunosorbent assay to measure the urinary excretion of clusterin after bilateral renal ischemia, in the (cy/ +) rat model of autosomal-dominant polycystic kidney disease and in the FHH rat model of focal segmental glomerulosclerosis. After bilateral renal ischemia, the urinary excretion of clusterin paralleled the excretion of total protein and albumin and correlated with the extent of tubular damage. Male (cy/ +) rats, but not female (cy/ +) rats, excreted more clusterin than age-matched (+/ +) rats, a finding consistent with the more rapid course of the disease in males. FHH rats presented with pronounced proteinuria and albuminuria but did not excrete increased levels of clusterin. Urinary clusterin levels could therefore serve as a valuable marker for the severity of tubular damage. Furthermore, clusterin may also help to differentiate between tubular and glomerular forms of proteinuria.

Animals↗
PubMed2004

Overexpression of clusterin in human hepatocellular carcinoma.

Clusterin has been reported to play a significant role in tumorigenesis, and its overexpression occurs in various human malignancies. We examine the clusterin overexpression in human hepatocellular carcinoma (HCC) and verify its clinical usefulness as a candidate biomarker by clinicopathologic and survival analysis. We examined clusterin overexpression immunohistochemically in 100 surgically resected HCCs using the tissue microarray method. A total of 89 HCCs exhibited clusterin overexpression, in 2 distinct staining patterns, cytoplasmic (n=35) and canalicular (n=54). Clusterin positivity demonstrated an inverse correlation with tumor cell apoptosis evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay (P=0.024). Within the clusterin-positive group, cytoplasmic overexpression had a positive correlation with tumor cell proliferative activity measured by the Ki-67 labeling index (P=0.003). HCCs demonstrating cytoplasmic clusterin overexpression were associated with poor Edmondson's histological grade and high TNM stage (P <0.05). In the survival analysis, the cytoplasmic-positive group demonstrated an overall poorer prognosis than the canalicular-positive group, according to univariate and multivariate analysis (P <0.05). In HCC, clusterin may play an important role in tumorigenesis and progression, corresponding to its subcellular localization. Cytoplasmic clusterin overexpression could be a potential new prognostic marker for the aggressiveness of HCC.

Apoptosis↗
PubMed2002

Suppression of clusterin expression enhanced cisplatin-induced cytotoxicity on renal cell carcinoma cells.

OBJECTIVES: To evaluate whether antisense transfection targeted against clusterin enhances the chemosensitivity in renal cell carcinoma. METHODS: Caki-1, a renal cell carcinoma cell line, and cisplatin were used as chemotherapeutic agents. Clusterin expression of Caki-1 cells after treatment with cisplatin was measured by Western blot analysis. After the construction of a clusterin suppression vector, clusterin expression was compared between Caki-1 cells transfected with the clusterin suppression vector (Caki-1/AS), Caki-1 cells transfected with control vector (Caki-1/VO), and parental Caki-1 cells. Tumor cell viability was measured with the MTT assay at 24 and 48 hours after cisplatin treatment. RESULTS: The expression of clusterin increased gradually in Caki-1 cells, peaking at 24 hours, and was reduced to an almost undetectable level at 48 hours after cisplatin treatment. Clusterin expression was suppressed, and the percentage of viable tumor cells decreased significantly more in the Caki-1/AS than in the Caki-1/VO or parental Caki-1 cells at 24 hours after cisplatin treatment. The change in chemosensitivity of the Caki-1/AS cells lost its significance at 48 hours after cisplatin treatment. CONCLUSIONS: Our results showed that clusterin expression increased transiently after treatment of cisplatin, and its suppression by antisense transfection enhanced the cisplatin-induced cytotoxicity of renal cell carcinoma cells. Clusterin suppression may be a useful modality in enhancing the effects of cytotoxic chemotherapy in renal cell carcinoma.

Blotting, Western↗
PubMed2003

Clusterin mRNA expression in apoptotic and activated rat thymocytes.

Clusterin is a 75-80 kDa heterodimeric glycoprotein, that is produced in most tissues but which exact biological role is still not clear. Particularly, its role in protection or promotion of apoptosis is heavily disputed, since data supporting both views have been reported in several independent studies. To clarify this issue, and also to determine whether clusterin expression itself might be affected by apoptosis, in the present study, rat thymocytes were treated with dexamethasone, -a synthetic glucocorticoid that elicits apoptosis in thymocytes-, and clusterin mRNA expression was analyzed by semi-quantitative RT-PCR before and after induction of apoptosis. Interestingly, neither the treatment with dexamethasone in vitro nor triggering of apoptosis in vivo up- regulated clusterin expression, opposing the view that clusterin is involved in apoptotic processes. On the other hand, a new clusterin mRNA isoform was detected and isolated, whose expression was restricted to freshly isolated thymocytes. This novel isoform lacks the post-translational proteolytic cleavage site and is therefore predicted to encode a monomeric protein. The biological function under normal circumstances, however, will need further investigations for clarification. While apoptosis could not modulate clusterin expression, activation of thymocytes with concanavalin A and interleukin-2 resulted in up-regulation of clusterin mRNA level, indicating that clusterin expression is rather under the control of cell activation-mediated rather than apoptosis-induced signals.

Amino Acid Sequence↗
PubMed2002

Suppression of apolipoprotein C-II amyloid formation by the extracellular chaperone, clusterin.

The effect of the extracellular chaperone, clusterin, on amyloid fibril formation by lipid-free human apolipoprotein C-II (apoC-II) was investigated. Sub-stoichiometric levels of clusterin, derived from either plasma or semen, potently inhibit amyloid formation by apoC-II. Inhibition is dependent on apoC-II concentration, with more effective inhibition by clusterin observed at lower concentrations of apoC-II. The average sedimentation coefficient of apoC-II fibrils formed from apoC-II (0.3 mg.mL-1) is reduced by coincubation with clusterin (10 microg x mL(-1)). In contrast, addition of clusterin (0.1 mg x mL(-1)) to preformed apoC-II amyloid fibrils (0.3 mg x mL(-1)) does not affect the size distribution after 2 days. This sedimentation velocity data suggests that clusterin inhibits fibril growth but does not promote fibril dissociation. Electron micrographs indicate similar morphologies for amyloid fibrils formed in the presence or absence of clusterin. The substoichiometric nature of the inhibition suggests that clusterin interacts with transient amyloid nuclei leading to dissociation of the monomeric subunits. We propose a general role for clusterin in suppressing the growth of extracellular amyloid.

Amyloid↗
PubMed2001

Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury.

BACKGROUND: Clusterin is a soluble complement regulatory protein that binds to C5b-7 and inhibits generation of membrane attack complex, C5b-9. Glomerular deposition of clusterin has been observed in human and experimental membranous nephropathy in association with C5b-9 and immune deposits. However, it is controversial as to whether clusterin observed in glomeruli is synthesized by the resident glomerular cells or is derived from the circulation. We examined whether clusterin is expressed by resident glomerular cells exposed to complement-mediated injury. METHODS: In vitro, cultured mesangial cells were exposed to antithymocyte serum immunoglobulin G and 5% normal rat serum as a complement source. In vivo, we induced anti-Thy1 nephritis in rats and examined the kidneys on days 8 and 29. RESULTS: We observed increased expression of clusterin in cultured rat glomerular mesangial cells stimulated by sublytic complement attack. We also demonstrated that in comparison with control rats, both a marked increase in clusterin mRNA in the glomeruli and marked deposition of clusterin protein in the mesangial area occurred in the OX-7-treated rats on day 8 in association with C5b-9 deposition and on day 29. CONCLUSION: Clusterin was induced in glomerular mesangial cells during the course of immune-mediated injuries. This up-regulation of clusterin may play a critical role in protecting mesangial cells from complement attack.

Animals↗
PubMed2002

Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice. Although Abeta deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Abeta (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Abeta structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.

Alzheimer Disease↗
PubMed1998

Clusterin biogenesis is altered during apoptosis in the regressing rat ventral prostate.

Clusterin was first characterized as an apoptosis-associated transcript after it was identified as testosterone-repressed prostate message (TRPM-2) that is expressed in the epithelial cells of the regressing rat ventral prostate. Increases in clusterin mRNA and protein have been consistently detected in apoptotic cell death paradigms, establishing clusterin gene expression as a prominent marker of apoptotic cell loss. However, enhanced protein expression has also been reported in surviving cells. This ambiguity makes it difficult to define the contribution of clusterin to apoptosis. To address this problem, a panel of polyclonal and monoclonal antibodies were raised against the clusterin alpha-chain, beta-chain, and mixed alpha/beta epitopes. These antibodies detect changes in the biogenesis of clusterin during apoptosis by Western analysis and immunohistochemistry. A 42-kDa glyco/isoform of clusterin appears to be up-regulated in dying epithelial cells. This glyco/isoform is apparently generated as a result of apoptosis-induced stimulation of a normal but under-utilized, synthetic pathway. These data demonstrate that clusterin synthesized by apoptotic cells can be immunologically distinguished from clusterin synthesized by surviving cells in damaged tissue.

Amino Acid Sequence↗
PubMed1999

Clusterin has chaperone-like activity similar to that of small heat shock proteins.

Clusterin is a highly conserved protein which is expressed at increased levels by many cell types in response to a broad variety of stress conditions. A genuine physiological function for clusterin has not yet been established. The results presented here demonstrate for the first time that clusterin has chaperone-like activity. At physiological concentrations, clusterin potently protected glutathione S-transferase and catalase from heat-induced precipitation and alpha-lactalbumin and bovine serum albumin from precipitation induced by reduction with dithiothreitol. Enzyme-linked immunosorbent assay data showed that clusterin bound preferentially to heat-stressed glutathione S-transferase and to dithiothreitol-treated bovine serum albumin and alpha-lactalbumin. Size exclusion chromatography and SDS-polyacrylamide gel electrophoresis analyses showed that clusterin formed high molecular weight complexes (HMW) with all four proteins tested. Small heat shock proteins (sHSP) also act in this way to prevent protein precipitation and protect cells from heat and other stresses. The stoichiometric subunit molar ratios of clusterin:stressed protein during formation of HMW complexes (which for the four proteins tested ranged from 1.0:1.3 to 1.0:11) is less than the reported ratios for sHSP-mediated formation of HMW complexes (1.0:1.0 or greater), indicating that clusterin is a very efficient chaperone. Our results suggest that clusterin may play a sHSP-like role in cytoprotection.

Animals↗
PubMed1999

Multiple involvement of clusterin in chicken ovarian follicle development. Binding to two oocyte-specific members of the low density lipoprotein receptor gene family.

The interaction of the female germ cell with somatic cells during the development of the ovarian follicle in the chicken provides a prime system to study gene expression. Here, we have uncovered the involvement of clusterin, the function(s) of which is still poorly understood, in this complex process. As revealed by molecular cloning, chicken clusterin is a 428-residue protein that migrates at 70 kDa on SDS-polyacrylamide gel electrophoresis and possesses most of the structural features of its mammalian successors. However, in contrast to mammalian clusterin, the chicken protein appears not to be cleaved intracellularly into a disulfide-linked heterodimer; possibly as a consequence thereof, it is not secreted constitutively and is absent from the circulation, where most of clusterin is found in mammals. In the ovary, clusterin is a major product of the somatic granulosa cells, in a pattern correlating with the developmental phases of individual follicles. In that, transcript levels are high not only at onset of vitellogenesis, but also in atretic follicles and in the postovulatory follicle sac, i.e. in situations characterized by apoptotic events. Yolk of growing oocytes contains a 43-kDa truncated form of clusterin that does not appear to be synthesized within the oocyte. Rather, we here show for the first time that 70-kDa clusterin interacts not only with megalin, but also with two chicken oocyte-specific members of the low density lipoprotein receptor (LDLR) gene family. These receptors, termed LDLR-related protein with eight ligand binding repeats (LR8) and LDLR-related protein (380 kDa), likely internalize granulosa cell-derived 70-kDa clusterin, which may subsequently be processed to the 43-kDa product. Thus, chicken clusterin could serve as a marker for follicular atresia and resorption, and, based on its ability to bind several other proteins, it may serve as carrier for the receptor-mediated endocytosis into oocytes of components important for embryonic development, two hitherto unknown functions of this intriguing protein.

Amino Acid Sequence↗
PubMed2002

Mildly acidic pH activates the extracellular molecular chaperone clusterin.

Many features of the chaperone action of clusterin are similar to those of the intracellular small heat shock proteins (sHSPs) that, like clusterin, exist in solution as heterogeneous aggregates. Increased temperature induces dissociation of some sHSP aggregates and an enhanced chaperone action, suggesting that a dissociated form is the active chaperone species. We recently reported that clusterin aggregates dissociate at mildly acidic pH. To further explore the similarities between clusterin and the sHSPs, we tested the effects of temperature and pH on the structure of clusterin and its chaperone action. Our results demonstrate that increased temperature does not induce dissociation of clusterin aggregates, or other major structural changes, and has little effect on its chaperone action. However, we show that the chaperone action of clusterin is enhanced at mildly acidic pH. Clusterin is the first chaperone shown to be activated by reduced pH. This unique mode of activation appears to result from an increase in regions of solvent-exposed hydrophobicity, which is independent of any major changes in secondary or tertiary structure. We propose a model in which low pH-induced dissociation of clusterin aggregates increases the abundance of the heterodimeric chaperone-active species, which has greater hydrophobicity exposed to solution.

Anilino Naphthalenesulfonates↗
PubMed2004

Synergistic antitumor activity by combined treatment with gemcitabine and antisense oligodeoxynucleotide targeting clusterin gene in an intravesical administration model against human bladder cancer kotcc-1 cells.

PURPOSE: We investigated whether antisense (AS) oligodeoxynucleotide (ODN) targeting the clusterin gene enhances the cytotoxic effect of gemcitabine in human bladder cancer KoTCC-1 cells in vitro and in vivo, and evaluated the usefulness of the combined administration of AS clusterin ODN and gemcitabine using an intraperitoneal tumor cell injection model. MATERIALS AND METHODS: The cytotoxic effect of combined treatment with AS clusterin ODN and gemcitabine on in vitro KoTCC-1 growth was examined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The in vivo growth inhibitory effects of combined AS clusterin ODN and gemcitabine therapy on subcutaneous KoTCC-1 tumor was also examined. The intraperitoneal tumor cell injection model, which mimics intravesical administration therapy against bladder cancer, was used to evaluate the efficacy of combined AS clusterin ODN and gemcitabine therapy. RESULTS: AS clusterin ODN treatment of KoTCC-1 cells significantly enhanced gemcitabine chemosensitivity in a dose dependent manner, decreasing gemcitabine IC50 by approximately 90%. In vivo systemic administration of AS clusterin ODN and gemcitabine significantly decreased subcutaneous KoTCC-1 tumor volume compared with scramble control ODN plus gemcitabine. Furthermore, combined administration of AS clusterin ODN plus gemcitabine resulted in significantly delayed formation of hemorrhagic ascites compared with scramble control ODN plus gemcitabine in an intraperitoneal tumor cell injection model. CONCLUSIONS: These findings suggest that AS clusterin ODN may be useful for enhancing the cytotoxicity of gemcitabine in patients with bladder cancer, particularly as a novel therapeutic strategy for intravesical instillation therapy.

Administration, Intravesical↗
PubMed1996

Clusterin (SGP-2) induction in rat astroglial cells exposed to prion protein fragment 106-126.

Prion-related encephalopathies are characterized by the accumulation of an abnormal prion protein isoform (PrPSc) associated with neuronal degeneration and astrogliosis. The synthetic peptide homologous to PrP fragment 106-126 (PrP 106-126) induced in vitro neuronal apoptosis and glial proliferation. We used Northern blot analysis and the RNA polymerase chain reaction to assess the expression of several genes associated with programmed cell death and proliferation. Blots of total RNA extracted from neuronal and astroglial cells exposed to PrP 106-126 for between 1 h and 7 days were hybridized with probes recognizing c-fos, c-jun, c-myc, p53, hsp-70 and bcl-2 mRNA. Except for a slight decrease in bcl-2 mRNA in neuronal cells, no change in other transcripts was evident. Since clusterin (apolipoprotein J) mRNA levels are increased in prion-related encephalopathies and clusterin immunoreactivity has been located in association with PrPSc in Gerstmann-Sträussler-Scheinker brain, the expression of clusterin was determined in neuronal and astroglial cells chronically exposed to PrP 106-126. Although the induction of clusterin has been involved in the apoptotic mechanism in other experimental conditions, its expression was unchanged in PrP 106-126-treated neurons, while a three-fold induction of clusterin mRNA was observed in astrocytes exposed to PrP 106-126. To investigate whether the clusterin up-regulation was simply associated with the astroglial proliferative stimulus of PrP 106-126 or was specifically induced by the peptide, we measured clusterin expression in astrocytes cultured in fetal calf serum-free medium and exposed to PrP 106-126 or fetal calf serum restoration. In this condition the PrP peptide, like fetal calf serum, increased the glial proliferation rate, but only PrP 106-126 doubled clusterin mRNA. The selectivity of this effect indicates that PrPSc is directly involved in the clusterin up-regulation seen in prion-related encephalopathies and is associated with astroglial cells.

Animals↗
PubMed2006

Clusterin expression in primary and metastatic melanoma.

Clusterin is a pleiotrophic glycoprotein that has been implicated in diverse physiologic processes. Recent studies of gene expression profiling found clusterin to be expressed in desmoplastic variants of malignant melanoma. In this study, we extended those observations and examined clusterin expression in a larger number of primary as well as in metastatic melanomas and melanocytic nevi. We used tissue microarray panels as well as selected conventional sections from formalin-fixed and paraffin-embedded tissue blocks. Positive staining for clusterin was found in seven of 21 (30%) primary desmoplastic and three of 21 (7%) non-desmoplastic melanoma. Among metastatic tumors, clusterin expression was found in five of 37 tumors (13.5%). Clusterin expression was not seen in melanocytes of normal skin or in any of the 10 melanocytic nevi tested. Clusterin expression was not entirely restricted to melanoma; it was also seen in a few non-neoplastic tissues, including perifollicular fibroblasts, occasional sebocytes, and the epithelial cells lining sebaceous duct and the isthmus of the hair follicle. Our findings confirm the observation that clusterin can be expressed in melanoma, in particular primary desmoplastic melanoma. However, clusterin appears to be present only in a minority of melanomas.

Biomarkers, Tumor↗
PubMed2004

Myc-transformed epithelial cells down-regulate clusterin, which inhibits their growth in vitro and carcinogenesis in vivo.

Effective treatment of malignant carcinomas requires identification of proteins regulating epithelial cell proliferation. To this end, we compared gene expression profiles in murine colonocytes and their c-Myc-transformed counterparts, which possess enhanced proliferative potential. A surprisingly short list of deregulated genes included the cDNA for clusterin, an extracellular glycoprotein without a firmly established function. We had previously demonstrated that in organs such as skin, clusterin expression is restricted to differentiating but not proliferating cell layers, suggesting a possible negative role in cell division. Indeed, its transient overexpression in Myc-transduced colonocytes decreased cell accumulation. Furthermore, clusterin was down-regulated in rapidly dividing human keratinocytes infected with a Myc-encoding adenovirus. Its knockdown via antisense RNA in neoplastic epidermoid cells enhanced proliferation. Finally, recombinant human clusterin suppressed, in a dose-dependent manner, DNA replication in keratinocytes and other cells of epithelial origin. Thus, clusterin appears to be an inhibitor of epithelial cell proliferation in vitro. To determine whether it also affects neoplastic growth in vivo, we compared wild-type and clusterin-null mice with respect to their sensitivity to 7, 12-dimethylbenz(a)anthracene /12-Otetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis. We observed that the mean number of papillomas/mouse was higher in clusterin-null animals. Moreover, these papillomas did not regress as readily as in wild-type mice and persisted beyond week 35. The rate of progression toward squamous cell carcinoma was not altered, although those developing in clusterin-null mice were on average better differentiated. These data suggest that clusterin not only suppresses epithelial cell proliferation in vitro but also interferes with the promotion stage of skin carcinogenesis.

Animals↗
PubMed2003

Nuclear translocation of a clusterin isoform is associated with induction of anoikis in SV40-immortalized human prostate epithelial cells.

Clusterin gene expression is potently induced in experimental models in which apoptosis is activated, such as rat prostate involution following castration. Nevertheless, its precise physiological role has not yet been established, and both anti-apoptotic and pro-apoptotic functions have been suggested for this gene. Clusterin expression level depends on cell proliferation state, and we recently showed that its over-expression inhibited cell cycle progression of SV40-immortalized human prostate epithelial cells PNT2 and PNT1a. Here we studied clusterin expression in PNT1a cells subjected to serum-starvation with the aim of defining clusterin early molecular changes following apoptosis induction. Under serum-starvation conditions, decreased growth rate, slow rounding-up of cells, cell detachment, and formation of apoptotic bodies indicative of anoikis (detachment-induced apoptosis) were preceded by significant downregulation of 70 kDa clusterin precursor and upregulation of 45-40 kDa isoforms. On the 8th day of serum-free culturing, only the higher molecular weight protein-band of about 45 kDa was clearly induced and accumulated in detached cells and apoptotic bodies in which PARP was activated. Anoikis was preceded by induction and transloction of a 45-kDa clusterin isoform to the nucleus. Thus, nuclear targeting of a specific 45-kDa isoform of clusterin appeared to be an early and specific molecular signal triggering anoikis-death. Considering also that clusterin is downregulated during prostate cancer onset and progression, and that its upregulation has inhibited DNA synthesis and cell cycle progression of immortalized human prostate epithelial cells, we suggest that clusterin might be a new anti-oncogene in the prostate.

Active Transport, Cell Nucleus↗
PubMed2005

Therapeutic efficacy of adenoviral-mediated p53 gene transfer is synergistically enhanced by combined use of antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model.

To establish a more effective therapeutic strategy against advanced bladder cancer, we investigated the effects of combined treatment with antisense (AS) oligodeoxynucleotide (ODN) targeting the anti-apoptotic gene clusterin and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) using the human bladder cancer KoTCC-1 model. Clusterin expression in KoTCC-1 cells was highly upregulated by Ad5CMV-p53 treatment; however, AS clusterin ODN treatment further suppressed clusterin expression in KoTCC-1 cells after Ad5CMV-p53 treatment. AS clusterin ODN treatment synergistically enhanced the cytotoxic effect of Ad5CMV-p53, and DNA fragmentation characteristic of apoptosis was observed only after combined treatment with AS clusterin ODN and Ad5CMV-p53, but not after treatment with either agent alone. Administration of AS clusterin ODN and Ad5CMV-p53 into nude mice resulted in a significant inhibition of KoTCC-1 tumor growth as well as lymph node metastases compared to administration of either agent alone. Furthermore, combined treatment with AS clusterin ODN, Ad5CMV-p53, and cisplatin completely eradicated KoTCC-1 tumors and lymph node metastases in 60% and 100% of mice, respectively. These findings suggest that combined treatment with AS clusterin ODN and Ad5CMV-p53 could be a novel strategy to inhibit bladder cancer progression, and that further additional use of a chemotherapeutic agent may substantially enhance the efficacy of this combined regimen.

Adenoviridae↗