Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study is to investigate cancer stem cells and their markers in the prostate cancer cell line Du145. Different populations of cells were isolated from Du145. The clones formed by CD44+ integrinalpha(2)beta(1)+CD133+ cells are remarkably different morphologically and quantitatively from those formed by integrinalpha(2)beta(1)(-/low)CD133(-) cells. CD133(+) cells have the capacity for self renewal, extensive differentiation potential, and high proliferative and tumorigenic potential. CD34+ and CD117+ cells have no stem cell properties. Expression levels of c-myc and beta-catenin were elevated and bax was down regulated in CD44+ integrinalpha(2)beta(1)+CD133+ cells. In summary, CD44, integrinalpha(2)beta(1) and CD133 could be the cancer stem cell makers for the Du145 cell line. CD133+ cells differed significantly from CD44+ integrinalpha(2)beta(1)(-/low)CD133- cells and the total population in clone generation, genes expression, differentiation, proliferative and tumorigenic potential.
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PMID:Cancer stem-like cells in human prostate carcinoma cells DU145: the seeds of the cell line? 1759 51

The surprising disparity between the number of protein-encoding genes ( approximately 30,000) in the human genome and the number of proteins ( approximately 300,000) in the human proteome has inspired the development of translational proteomics aimed at protein expression profiling of disease states. Translational proteomics, which offers the promise of early disease detection and individualized therapy, requires new methods for the analysis of clinical specimens. We have developed quantitative fluorescence imaging analysis (QFIA) for accurate, reproducible quantification of proteins in slide-mounted tissues. The method has been validated for the analysis of beta-catenin in archived prostate specimens fixed in formalin. QFIA takes advantage of the linearity of fluorescence antibody signaling for tissue epitope content, a feature validated for beta-catenin in methacarn-fixed prostate specimens analyzed by reverse-phase protein array analysis and QFIA (r = 0.97). QFIA of beta-catenin in formaldehyde-fixed tissues correlated directly with beta-catenin content (r = 0.86). Application of QFIA in a cross-sectional study of biopsies from 42 prostate cancer (PC) cases and 42 matched controls identified beta-catenin as a potential field marker for PC. Receiver operating characteristic plots revealed that beta-catenin expression in the normal-appearing acini of cancerous glands identified 42% (95% confidence intervals, 26-57%) of cancer cases, with 88% (95% confidence intervals, 80-96%) specificity. The marker may contribute to a PC biomarker panel. In conclusion, we report the development and validation of a new method for fluorescence quantification of proteins in archived tissues and its application to archived specimens for an evaluation of beta-catenin expression as a biomarker for PC.
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PMID:Quantitative fluorescence imaging analysis for cancer biomarker discovery: application to beta-catenin in archived prostate specimens. 1762 4

Deregulation of beta-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 microg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 micromol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of beta-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to beta-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking beta-catenin signaling.
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PMID:Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. 1763 4

Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/beta-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/beta-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression.
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PMID:Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation. 1764 14

Versican, one of the key components of prostatic stroma, plays a central role in tumor initiation and progression. Here, we investigated promoter elements and mechanisms of androgen receptor (AR)-mediated regulation of the versican gene in prostate cancer cells. Using transient transfection assays in prostate cancer LNCaP and cervical cancer HeLa cells engineered to express the AR, we demonstrate that the synthetic androgen R1881 and dihydrotestosterone stimulate expression of a versican promoter-driven luciferase reporter vector (versican-Luc). Further, both basal and androgen-stimulated versican-Luc activities were significantly diminished in LNCaP cells, when AR gene expression was knocked down using a short hairpin RNA. Methylation-protection footprinting analysis revealed an AR-protected element between positions +75 and +102 of the proximal versican promoter, which strongly resembled a consensus steroid receptor element. Electrophoretic mobility shift and supershift assays revealed strong and specific binding of the recombinant AR DNA binding domain to oligonucleotides corresponding to this protected DNA sequence. Site-directed mutagenesis of the steroid receptor element site markedly diminished R1881-stimulated versican-Luc activity. In contrast to the response seen using LNCaP cells, R1881 did not significantly induce versican promoter activity and mRNA levels in AR-positive prostate stromal fibroblasts. Interestingly, overexpression of beta-catenin in the presence of androgen augmented versican promoter activity 10- and 30-fold and enhanced versican mRNA levels 2.8-fold in fibroblasts. In conclusion, we demonstrate that AR transactivates versican expression, which may augment tumor-stromal interactions and may contribute to prostate cancer progression.
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PMID:Androgen receptor regulation of the versican gene through an androgen response element in the proximal promoter. 1772 59

Alterations in the Wnt/beta-catenin pathway are associated with the development and progression of human prostate cancer. Decursin, a pyranocoumarin isolated from the Korean Angelica gigas root, inhibits the growth of androgen-independent human prostate cancer cells, but little is known about its mechanism of action. Using a cell-based screen, we found that decursin attenuates the Wnt/beta-catenin pathway. Decursin antagonized beta-catenin response transcription (CRT), which was induced with Wnt3a-conditioned medium and LiCl, by promoting the degradation of beta-catenin. Furthermore, decursin suppressed the expression of cyclin D1 and c-myc, which are downstream target genes of beta-catenin and thus inhibited the growth of PC3 prostate cancer cells. In contrast, decursinol, in which the (CH3)2-C=CH-COO- side chain of decursin is replaced with -OH, had no effect on CRT, the level of intracellular beta-catenin, or PC3 cell proliferation. Our findings suggest that decursin exerts its anticancer activity in prostate cancer cells via inhibition of the Wnt/beta-catenin pathway.
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PMID:Decursin suppresses human androgen-independent PC3 prostate cancer cell proliferation by promoting the degradation of beta-catenin. 1785 53

Prostate cancer is initially dependent on androgens for growth; hence, recurrent prostate is treated with androgen ablation which may result in progression to androgen independence characterized by a resistance to such therapy. Androgens bind to and activate the androgen receptor (AR), a member of the nuclear steroid receptor family of transcription factors, which regulates prostate cancer cell proliferation and survival in androgen-independent, as well as -dependent, tumors. Another pathway regulating proliferation and survival is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Here we analyze reports in the literature indicating that these two pathways cooperate to regulate prostate tumor development and progression. Studies show that AR transcriptional activity and expression are regulated by Akt. In addition, androgens regulate the Akt pathway by both genomic and non-genomic effects. This explains why prostate tumors subjected to androgen ablation experience an increase in Akt phosphorylation, and suggest that the tumor compensates for the loss of one pathway with another. Different modes of interaction between the two pathways, including direct interaction, or regulation via downstream intermediates, such as the wnt/GSK-3beta/beta-catenin pathway, NF-kappaB, and the FOXO family of transcription factors, will be discussed. In addition, we will discuss the role of Akt in the interaction of the AR with upstream regulators of Akt phosphorylation, such as receptor tyrosine kinases of the EGF and IGF-1 receptor families and the tumor suppressor PTEN.
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PMID:Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. 1789 24

In vitro invasion and adhesion of stably semaphorin (sema) 3E-transfected PC-3 prostate cancer cells were determined in the presence and absence of transferrin. Invasion and adhesion decreased compared to untransfected cells; however, transferrin reversed the effects. Transferrin differentially regulated E-cadherin and beta-catenin in these cells. Insulin growth factor 3 (IGFBP3) negated the invasive and adhesive effects of transferrin. Transferrin increased binding of insulin growth factor (IGF)-1 to the activated IGF-1 receptor, and IGF-1 mimicked the invasive and adhesive effects of transferrin. These data suggest that transferrin modulates sema3E-transfected cells through an IGFBP3/IGF-1-dependent pathway, in part, by regulation of adhesion proteins.
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PMID:Transferrin reverses the anti-invasive activity of human prostate cancer cells that overexpress sema3E. 1791 56

2-Methoxyestradiol (2-ME(2)) is a novel anticancer agent because of its ability to potentiate apoptotic cell death and inhibit cancer cell growth and angiogenesis. The modes of action of this agent, however, have not yet been fully elucidated. In our study, we have investigated whether 2-ME2 is able to modulate beta-catenin signaling in prostate cancer cells, which is one of the major players in cell-cell adhesion, proliferation, apoptosis and carcinogenesis. We found that beta-catenin levels were significantly upregulated by 2-ME(2) in a dose-dependent manner in androgen dependent and independent prostate cancer total cellular extracts. We further show that beta-catenin levels were significantly increased in the membrane fraction, while nuclear fractions of beta-catenin were downregulated in the 2-ME(2)-treated cells. Accumulation of dephospho-beta-catenin (nondegraded form) parallel with Bcl-2 and Cyclin D1 downregulation was also achieved after 2-ME(2) treatment. Moreover, we demonstrate that the beta-catenin production by 2-ME(2) is mediated through the MEK/ERK-2 signaling pathway. Collectively, these results suggest that the cytostatic effect of 2-ME(2) may be mediated through the prevention of the translocation of beta-catenin to the nucleus parallel with an increase in cell-cell adhesion by increasing membrane beta-catenin production, eventually preventing cell migration. Moreover, dephospho-beta-catenin accumulation by 2ME(2) in the cytoplasm may contribute to the induction of apoptosis of these cells. Finally, studies testing the efficacy of 2-ME(2) in human prostate cancer are warranted to determine whether the inhibition of the expected loss of membranous beta-catenin and the upregulation of nuclear beta-catenin can prevent prostate cancer development and progression.
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PMID:2-Methoxyestradiol modulates beta-catenin in prostate cancer cells: a possible mediator of 2-methoxyestradiol-induced inhibition of cell growth. 1793 27

We have previously demonstrated that Protein Kinase D1 (PKD1) interacts with E-cadherin and is associated with altered cell aggregation and motility in prostate cancer (PC). Because both PKD1 and E-cadherin are known to be dysregulated in PC, in this study we investigated the functional consequences of combined dysregulation of PKD1 and E-cadherin using a panel of human PC cell lines. Gain and loss of function studies were carried out by either transfecting PC cells with full-length E-cadherin and/or PKD1 cDNA or by protein silencing by siRNAs, respectively. We studied major malignant phenotypic characteristics including cell proliferation, motility, and invasion at the cellular level, which were corroborated with appropriate changes in representative molecular markers. Down regulation or ectopic expression of either E-cadherin or PKD1 significantly increased or decreased cell proliferation, motility, and invasion, respectively, and combined down regulation cumulatively influenced the effects. Loss of PKD1 or E-cadherin expression was associated with increased expression of the pro-survival molecular markers survivin, beta-catenin, cyclin-D, and c-myc, whereas overexpression of PKD1 and/or E-cadherin resulted in an increase of caspases. The inhibitory effect of PKD1 and E-cadherin on cell proliferation was rescued by coexpression with beta-catenin, suggesting that beta-catenin mediates the effect of proliferation by PKD1 and E-cadherin. This study establishes the functional significance of combined dysregulation of PKD1 and E-cadherin in PC and that their effect on cell growth is mediated by beta-catenin.
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PMID:Beta-catenin mediates alteration in cell proliferation, motility and invasion of prostate cancer cells by differential expression of E-cadherin and protein kinase D1. 1797 46


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