Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clusterin (CLU) protein is widely distributed in animal tissues and is involved in many different processes, including apoptosis and neoplastic transformation. Green tea catechins (GTC) are known to exert chemopreventive effects in many cancer models, including transgenic adenocarcinoma mouse prostate (TRAMP) mice that spontaneously develop prostate cancer (CaP). We report here that growth of SV40-immortalized human prostate epithelial cells (PNT1A) as well as tumorigenic, poorly differentiated prostate cancer cells (PC-3) was potently inhibited by EGCG, the major green tea catechin, while normal human prostate epithelial cells were not significantly affected. IC(50) doses of EGCG for 24 h caused caspase cascade activation and CLU protein accumulation in both cells lines but not in normal cells, in which CLU remained undetectable. While 100% of TRAMP mice developed CaP, only 20% of those receiving 0.3% GTC in drinking water developed the neoplasm. In TRAMP mice, the CLU gene was dramatically down-regulated during onset and progression of CaP. In GTC-treated TRAMP mice in which tumor progression was chemoprevented, CLU mRNA and protein progressively accumulated in the prostate gland. CLU dropped again to undetectable levels in animals in which GTC chemoprevention failed and CaP developed. Up-regulation of histone H3 and down-regulation of growth arrest-specific gene 1 (Gas1) mRNAs in CaP-developing TRAMP mice demonstrated a high proliferation rate in tumors, while the opposite occurred in the glands of GTC chemoprevented animals. Failure of GTC chemoprevention caused induction of both histone H3 and Gas1 and down-regulation of CLU. Immunohistochemistry experiments confirmed CLU down-regulation during CaP onset and progression, and CLU sustained expression in chemoprevented TRAMP mice. A possible role for CLU as a novel tumor-suppressor gene in the prostate is thus suggested.
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PMID:The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. 1535 31

The secreted clusterin/apolipoprotein J (CLU) protein form is a ubiquitously expressed heterodimeric glycoprotein which is differentially regulated in many severe physiological disturbance states including cell death, ageing, cancer progression, and various neurological diseases. Despite extensive efforts CLU function remains an enigma, the main cause being the intriguingly distinct and usually opposed functions in various cell types and tissues. In the current report we investigated the effects of CLU on cellular growth and survival in three human osteosarcoma (OS) cell lines, namely KH OS, Sa OS, and U-2 OS that express very low, moderate, and high endogenous steady-state CLU amounts, respectively. We found that exposure of these established OS cell lines or primary OS cells to genotoxic stress results in CLU gene induction at distinct levels that correlate negatively to CLU endogenous amounts. Following CLU-forced overexpression by means of an artificial transgene, we found that although extracellular CLU inhibits cell death in all three OS cell lines, intracellular CLU has different effects on cellular proliferation and survival in these cell lines. Transgenic KH OS cell lines adapted to moderate intracellular CLU levels were growth-retarded and became resistant to genotoxic and oxidative stress. In contrast, transgenic Sa OS and U2 OS cell lines adapted to high intracellular CLU amounts were sensitive to genotoxic and oxidative stress. In these two cell lines, the proapoptotic CLU function could be rescued by caspase inhibition. To monitor the immediate effects of heterologous CLU overexpression prior to cell adaptation, we performed transient transfections in all three OS cell lines. We found that induction of high intracellular CLU amounts increases spontaneous apoptosis in KH OS cells and reduces DNA synthesis in all three cell lines assayed. On the basis of these novel findings we propose that although extracellular CLU as well as intracellular CLU at low/moderate levels is cytoprotective, CLU may become highly cytostatic and/or cytotoxic if it accumulates intracellularly in high amounts either by direct synthesis or by uptake from the extracellular milieu.
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PMID:Differential effects of clusterin/apolipoprotein J on cellular growth and survival. 1564 46

Over the past 20 years, research on hormonal treatments for prostate cancer focused on maximizing androgen ablation through combination therapy. Unfortunately, maximal androgen ablation increases treatment-related side effects and expense and has not significantly prolonged time to androgen-independent (AI) progression. Intermittent androgen suppression (IAS) is based on the hypothesis that if tumor cells surviving androgen withdrawal can be forced along a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored, androgen dependence may be prolonged and progression to androgen independence may be delayed. Observations from animal model studies suggest that progression to androgen independence is delayed by IAS and this strategy is now being evaluated in phase III trials. Another strategy for improving therapies in advanced prostate cancer involves targeting genes that are activated by either androgen withdrawal or chemotherapy to delay or prevent the emergence of the resistant AI phenotype. Targeted inhibition of stress-associated increases in gene expression precipitated by androgen withdrawal or chemotherapy may enhance treatment-induced apoptosis and delay progression to AI disease. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, clusterin, Hsp27, and IGFBP-2 and IGFBP-5. The purpose of this paper is to review the rationale and progress in using targeted gene therapies to enhance tumor cell death after androgen withdrawal or taxane chemotherapy. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those not amenable to small molecule or antibody inhibition. The current status and future direction of several antisense oligonucleotides that have potential clinical use in cancer are also reviewed.
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PMID:Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer. 1627 54

Clusterin/apolipoprotein J (CLU) gene has a nearly ubiquitous expression pattern in human tissues. The two main CLU protein isoforms in human cells include the conventional glycosylated secreted heterodimer (sCLU) and a truncated nuclear form (nCLU). CLU has been implicated in various physiological processes and in many severe physiological disturbance states including ageing, cancer progression, vascular damage, diabetes, kidney and neuron degeneration. Although unrelated in their etiology and clinical manifestation, these diseases represent states of increased oxidative stress, which in turn, promotes amorphous aggregation of target proteins, increased genomic instability and high rates of cellular death. Among the various properties attributed to CLU so far, those mostly investigated and invariably appreciated are its small heat shock proteins-like chaperone activity and its involvement in cell death regulation, which are both directly correlated to the main features of oxidant injury. Moreover, the presence of both a heat shock transcription factor-1 and an activator protein-1 element in the CLU gene promoter indicate that CLU gene can be an extremely sensitive biosensor to reactive oxygen species. This review emphasizes on CLU gene regulation by oxidative stress that is the common link between all pathological conditions where CLU has been implicated.
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PMID:Regulation of clusterin/apolipoprotein J, a functional homologue to the small heat shock proteins, by oxidative stress in ageing and age-related diseases. 1709 Apr 21

Clusterin/Apolipoprotein J (CLU) is differentially regulated during in vivo cancer progression. We have addressed the role of CLU during the acquisition and maintenance of human cancer cells resistance to chemotherapeutic drugs. We used two osteosarcoma (OS) cell lines, namely U-2 OS and KH OS, and selected three generations of doxorubicin (DXR)-resistant cells (R1, R2 and R3; resistant to 0.0035, 0.035 and 0.35 microM DXR, respectively) by continuous exposure to increasing, clinically relevant, DXR concentrations. Our studies showed that the DXR-resistant OS cell lines were cross-resistant to a variety of unrelated cytotoxic agents. Analysis of the CLU mRNA and protein expression levels revealed a minimal CLU up-regulation in the U-2 OS R2 cells and a significant, more than 4-fold, induction in the KH OS R2 and R3 cells. Antibody-mediated neutralization of the extracellular CLU, or silencing of CLU gene expression via small interfering RNA (siRNA) partially sensitized KH OS R2 cells to the drugs assayed. Moreover, siRNA-mediated CLU knock down in the absence of DXR induced high levels of endogenous spontaneous apoptosis in both the parental and R2 OS cell lines. This effect was enhanced by more than 60% in the KH OS R2 cells as compared to their parental counterparts, indicating that the high CLU levels in the KH OS R2 cells are essential for survival. Overall, we suggest that CLU up-regulation in the multi-drug resistant OS cells relates to enhanced drug resistance. Therefore, CLU may represent a predictive marker, which correlates to response of cancer cells to chemotherapy.
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PMID:Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of Clusterin/Apolipoprotein J. 1709 23

The ubiquitously expressed glycoprotein Clusterin (CLU) is implicated in diverse cellular processes, yet its genuine molecular function remains undefined. CLU expression has been associated with various human malignancies, yet the mechanisms by which CLU promotes cancer progression and metastasis are not elucidated. In this study, using human lung adenocarcinoma cell lines as a model, we explored the involvement of CLU in modulating invasiveness of cancer cells. We discovered that CLU levels positively correlated with the degree of invasiveness in human lung adenocarcinoma cell lines. The observation that CLU-rich cells displayed a spindle-shape morphology while those with low CLU levels were cuboidal in shape prompted us to investigate if CLU modulates epithelial-to-mesenchymal transitions (EMT). CLU silencing by siRNA in a highly invasive, CLU-rich lung adenocarcinoma cell line induced a mesenchymal-to-epithelial transition (MET) evidenced by the spindle-to-cuboidal morphological change, increased E-cadherin expression, and decreased fibronectin expression. Compared with the vector-transfected cells, CLU-knocked-down (CLUi) cells showed reduced migration and invasion in vitro, as well as decreased metastatic potential in experimental metastasis. Re-expression of CLU in CLUi cells reversed the MET and restored the mesenchymal and invasive phenotypes. We found that Slug, a zinc-finger-containing transcriptional repressor of E-cadherin, was downregulated in CLUi cells. We also discovered that levels of activated ERK correlated with those of CLU and Slug. Taken together, our data suggest that CLU may regulate EMT and aggressive behaviour of human lung adenocarcinoma cells through modulating ERK signalling and Slug expression.
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PMID:Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway. 1916 32

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.
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PMID:Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer. 1939 Nov 38

The transition from normal to malignant phenotype implies the activation of some pathways that underlie the aberrant clone expansion. In some way, the conventional function of proteins involved in DNA repair, cell death/growth induction, vascularization, and metabolism is inhibited or shifted toward other pathways by soluble mediators that orchestrate such change depending on the microenvironment conditions. The adenoma-carcinoma sequence of the colon represents one of the most well studied and characterized models of human tumor progression. In this section, we focus our attention on defined pathways that underlie the initiation, promotion, and progression of colon cancer, conferring aggressiveness to the neoplastic cells. Clusterin (CLU) is a pleiotropic protein with a broad range of functions. It has recently drawn much attention because of its association with cancer promotion and metastasis. It is involved in prosurvival and apoptosis processes that are carried out by two different forms. sCLU is cytoprotective and its prosurvival function is the basis of the current Phase I/II clinical trials. In colorectal cancer an increase of sCLU expression occurs, whereas the nuclear proapoptotic form is downregulated. Several controversial data have been published on colon cancer discussing its role as tumor suppressor or prosurvival factor in colon cancer. Here, we report the dynamic interaction of the different forms of CLU with their partners DNA-repair protein Ku70 and proapoptotic factor Bax during colon cancer progression, which seems to be a crucial point for the neoplastic cell fate. We also highlight that the appearance and the progressive increase of the sCLU in colorectal tumors correlate to a significant increase of CLU in serum and stool of patients. On the basis of results obtained by CLU immuno-dosage in blood and stool of colon cancer patients, we report that sCLU could represent a diagnostic molecular marker for colon cancer screening.
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PMID:CLU and colon cancer. The dual face of CLU: from normal to malignant phenotype. 1987 22

Cancer cells need to interact synergistically with their surrounding microenvironment to form a neoplasm and to progress further to colonize distant organs. The microenvironment can exert profound epigenetic effects on cells through cell-derived interactions between cells, or through cell-derived factors deposited into the microenvironment. Tumor progression implies immune-escaping and triggers several processes that synergistically induce a cooperation among transformed and stromal cells, that compete for space and resources such as oxygen and nutrients. Therefore, the extra cellular milieu and tissue microenvironment heterotypic interactions cooperate to promote tumor growth, angiogenesis, and cancer cell motility, through elevated secretion of pleiotropic cytokines and soluble factors. Clusterin (CLU), widely viewed as an enigmatic protein represents one of the numerous cellular factors sharing the intracellular information with the microenvironment and it has also a systemic diffusion, tightly joining the "In and the Out" of the cell with a still debated variety of antagonistic functions. The multiplicity of names for CLU is an indication of the complexity of the problem and could reflect, on one hand its multifunctionality, or alternatively could mask a commonality of function. The posited role for CLU, further supported as a cytoprotective prosurvival chaperone-like molecule, seems compelling, in contrast its tumor suppressor function, as a guide of the guardians of the genome (DNA-repair proteins Ku70/80, Bax cell death inducer), could really reflect the balanced expression of its different forms, most certainly depending on the intra- and extracellular microenvironment cross talk. The complicated balance of cytokines network and the regulation of CLU forms production in cancer and stromal cells undoubtedly represent a potential link among adaptative responses, genomic stability, and bystander effect after oxidative stresses and damage. This review focuses on the tumor-microenvironment interactions strictly involved in controlling local cancer growth, invasion, and distant metastases that play a decisive role in the regulation of CLU different forms expression and release. In addition, we focus on the pleiotropic action of the extracellular form of this protein, sCLU, that may play a crucial role in redirecting stromal changes, altering intercellular communications binding cell surface receptors and contributing to influence the secretion of chemokines in paracrine and autocrine fashion. Further elucidation of CLU functions inside and outside ("in and out") of cancer cell are warranted for a deeper understanding of the interplay between tumor and stroma, suggesting new therapeutic cotargeting strategies.
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PMID:CLU "in and out": looking for a link. 1987 25

PSA, the only relevant marker for prostate cancer, has a low predictive value; moreover its low threshold leads to unnecessary biopsies with associated complications. Identification of prognostic factors is an important goal in prostate cancer. In the search for new markers, clusterin, has some potential as it is closely linked with cancer progression and resistance to apoptosis. We looked at the expression of secreted clusterin (sCLU) in prostate cells to determine correlations with progression and drug resistance. The plasmatic expression of sCLU was also investigated in order to use it as a potential marker for prostate cancer. sCLU expression was studied using Western blotting on cultured prostate cells, PWR-1E, PC3 and PC3 Docetaxel resistant cells in the cytosol and culture medium. An inhouse ELISA test was developed to determine sCLU expression in culture media and plasma samples. A patient cohort was identified from the Prostate Cancer Research Consortium Bio-Resource and plasmatic expression of sCLU was studied using western blotting and the inhouse ELISA test. Only the fully processed form of sCLU was identified in the medium of cells with increased expression associated with increased progression of disease and resistance to docetaxel. Plasmatic expression of sCLU was significantly higher in the plasma of patients with high grade prostate cancer with extracapsular extension than in the plasma of prostate cancer patients without extracapsular extension. Plasmatic sCLU may be an effective prognostic marker of prostate cancer and needs to be tested in a multimarker approach.
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PMID:Detecting soluble clusterin in in-vitro and in-vivo models of prostate cancer. 2056 4


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