Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 EGR1 transactivator is overexpressed in prostate cancer, and its expression pattern suggests that EGR1 could potentially regulate a number of steps involved in initiation and progression of prostate cancer, such as mitogenesis, invasiveness, angiogenesis, and metastasis. To identify potential EGR1 target genes in an unbiased manner, we have utilized adenovirus-mediated expression of EGR1 in a prostate cancer cell line to identify specific genes that are induced by EGR1. Using oligonucleotide arrays, a number of EGR1-regulated genes were identified and their regulation was confirmed by quantitative reverse transcription-polymerase chain reaction analysis. One of the largest gene classes identified in this screen includes several neuroendocrine-associated genes (neuron-specific enolase, neurogranin), suggesting that EGR1 overexpression may contribute to the neuroendocrine differentiation that often accompanies prostate cancer progression. This screen also identified several growth factors such as insulin-like growth factor-II, platelet-derived growth factor-A, and transforming growth factor-beta1, which have previously been implicated in enhancing tumor progression. The insulin-like growth factor-II gene lies within the 11p15.5 chromosomal locus, which contains a number of other imprinted genes, and EGR1 expression was found to induce at least two other genes in this locus (IPL, p57(KIP2)). Based on our results, coupling adenoviral overexpression with microarray and quantitative reverse transcription-polymerase chain reaction analyses could be a versatile strategy for identifying target genes of transactivators.
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PMID:EGR1 target genes in prostate carcinoma cells identified by microarray analysis. 1098 81

Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.
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PMID:Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. 1105 49

Further well designed studies are urgently needed to clarify if use of prostate-specific antigen (PSA) as a diagnostic test for prostate cancer can be improved by incorporating measurements of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding-protein 3 (IGFBP-3), and if these measurements might also identify men at higher risk.
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PMID:Can measurements of IGF-1 and IGFBP-3 improve the sensitivity of prostate-cancer screening? 1137 64

A marked decrease in the type 1 insulin-like growth factor (IGF) receptor (IGF-IR) occurs in prostate epithelial cells during transformation from the benign to the metastatic state. One of the principal regulators of IGF-IR gene expression, the WT1 tumor suppressor, is expressed in prostate cancer and in prostate cancer cell lines. The purpose of this study was to determine whether the decrease in IGF-IR expression was transcriptionally regulated, and whether WT1 action may be involved in the repression of the IGF-IR gene in prostate cancer cells. The P69 cell line was derived by immortalization of human primary prostate epithelial cells with simian virus-40 T antigen and is rarely tumorigenic. The M12 line was derived from the P69 line by selection for tumor formation in nude mice and is tumorigeneic and metastatic. P69 cells express 20,000 IGF-IR/cell, whereas M12 cells express 3,500 IGF-IR/cell. These differences in receptor number are reflected in proportional differences in IGF-IR mRNA levels. To assess IGF-IR promoter activity in these cell lines, each was transiently transfected with luciferase reporter vectors containing the IGF-IR gene transcription start site and 476 bp of 5'-flanking sequence, 640 bp of 5'-untranslated region sequence, or both regions. The promoter activity of the full-length construct was 50% lower (P < 0.01) in M12 cells compared with P69 cells, the activity of the 5'-flanking region construct was 53% lower (P < 0.0001), and that of the 5'-untranslated region construct was 36% lower (P = 0.01). P69 clones stably transfected with a WT1 expression vector exhibited decreased expression of the endogenous IGF-IR gene and decreased promoter activity in transient transfection assays with IGF-IR promoter constructs containing multiple WT1 binding sites. The observed reduction in endogenous IGF-IR expression was sufficient to inhibit IGF-I-stimulated cell proliferation. These data suggest that most of the decreased expression of the IGF-IR seen in malignant prostate epithelium is the result of transcriptional repression of the IGF-IR gene, and that this repression may be due in part to the increased expression of the WT1 tumor suppressor in metastatic prostate cancer.
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PMID:Transcriptional regulation of insulin-like growth factor-I receptor gene expression in prostate cancer cells. 1114 62

In view of evidence indicating significant involvement of the insulin-like growth factor (IGF) system in the pathogenesis of prostate cancer, we measured serum IGF-I and IGF-binding protein-3 (IGFBP-3) in men with benign prostatic hyperplasia (BPH; n = 75) or prostatic carcinoma (CaP; n = 84). The age-matched patient populations were selected to have circulating prostate-specific antigen (PSA), the most reliable predictor of CaP, in the overlapping diagnostic gray zone range of approximately 4--10 microg/L. Of particular interest was investigation of intact, fragment, and total IGFBP-3 levels in relation to PSA, which is also a well established IGFBP-3 protease. Among the key findings were significantly higher IGF-I and intact IGFBP-3 levels in CaP vs. BPH (P < 0.001), whereas changes in fragment and total IGFBP-3 were statistically insignificant. As expected, total PSA levels were similar in the two groups of patients (P = 0.173), whereas free PSA levels were significantly lower in those with CaP (P < 0.001). IGF-I and IGFBP-3 (intact and total) correlated significantly (P = 0.024 to <0.001) and inversely (r = -0.26 to -0.35) with free PSA in BPH, but not in CaP, and no correlations were found in comparisons involving total PSA. Statistical analysis of the various markers and their combinations indicated enhanced performance of IGF-I/free PSA [receiver operating characteristics area under the curve (AUC) = 0.728] and intact IGFBP-3/free PSA (AUC = 0.737) ratios in discriminating between BPH and CaP compared with the currently used free/total PSA ratio (AUC = 0.689). Multivariate logistic regression models confirmed the observed relationships and identified IGF-I/free PSA and intact IGFBP-3/free PSA as independent factors in predicting the presence of CaP. We conclude that increases in IGF-I and intact IGFBP-3 levels are positively associated with the presence of CaP in this group of patients with low to moderately elevated PSA, and that their measurements in relation to PSA may help improve diagnostic discrimination between BPH and prostate cancer.
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PMID:Insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in benign prostatic hyperplasia and prostate cancer. 1115 33

The insulin-like growth factor (IGF) system has been shown to regulate prostate cancer cell growth in vitro and, possibly, in vivo. In this study we examined RNA expression of IGF ligands and their receptors in 23 paired benign and neoplastic prostate tissues. In addition to comparing gene expression of IGF ligands and receptors between benign and neoplastic tissue samples, we correlated IGF-I, IGF-II, IGFR-1, and IGFR-2 RNA levels in tumor samples with prognostic clinico-pathological parameters such as stage, grade, Gleason score, perineural or extraprostatic invasion. We found higher IGF-I RNA levels in benign vs. malignant tissues (p = 0.014), whereas IGF-II RNA expression was higher in tumors with high Gleason score (GS) (p = 0.045). Using the Spearman rank correlation test we also found a positive correlation between IGFR-2 RNA levels and GS (p = 0.01). No correlation was found between expression of IGF ligands and receptors and tumor grade, stage perineural invasion, or extraprostatic involvement. We conclude that differential expression of certain IGF system components may be important in the biology and clinical behavior of prostate cancer.
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PMID:Gene expression of insulin-like growth factors and receptors in neoplastic prostate tissues: correlation with clinico-pathological parameters. 1129 53

G-protein coupled receptor (GPCR) agonists such as neuropeptides activate the insulin-like growth factor-1 receptor (IGF-IR) or the serine-threonine protein kinase Akt, suggesting that neuropeptides-GPCR signaling can cross-communicate with IGF-IR-Akt signaling pathways. Neutral endopeptidase 24.11 (NEP) is a cell-surface peptidase that cleaves and inactivates the neuropeptides endothelin-1 (ET-1) and bombesin, which are implicated in progression to androgen-independent prostate cancer (PC). We investigated the mechanisms of NEP regulation of neuropeptide-mediated cell survival in PC cells, including whether neuropeptide substrates of NEP induce phosphorylations of IGF-IR and Akt in PC cells. Western analyses revealed ET-1 and bombesin treatment induced phosphorylation of IGF-IRbeta and Akt independent of IGF-I in TSU-Pr1, DU145, and PC-3 PC cells, which lack NEP expression, but not in NEP-expressing LNCaP cells. Recombinant NEP and induced NEP expression in TSU-Pr1 cells using a tetracycline-repressive expression system inhibited ET-1-mediated phosphorylation of IGF-IRbeta and Akt, and blocked the protective effects of ET-1 against apoptosis induced by serum starvation. Incubation of TSU-Pr1 cells with specific kinase inhibitors together with ET-1 or bombesin showed that IGF-IR activation is required for neuropeptide-induced Akt phosphorylation, and that neuropeptide-induced Akt activation is predominantly mediated by Src and phosphatidylinositol 3-kinase but not by mitogen-activated protein kinase or protein kinase C. These data show that the neuropeptides ET-1 and bombesin stimulate ligand-independent activation of the IGF-IR, which results in Akt activation, and that this cross-communication between GPCR and IGF-IR signaling is inhibited by NEP.
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PMID:Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factor receptor-Akt cell survival pathway. 1130 83

LNCaP cells are human prostatic cancer cells that have a frame-shift mutation of the tumor suppressor gene PTEN and do not express the insulin receptor substrate-1 (IRS-1), a major substrate of the type 1 insulin-like growth factor receptor (IGF-IR). Ectopic expression of IRS-1 in LNCaP cells increases cell adhesion and decreases cell motility by an IGF-I-independent mechanism. We show now that these effects of IRS-1 are accompanied by serine phosphorylation of IRS-1 and are inhibited by inhibitors of phosphatidylinositol 3-kinase (PI3K). We have confirmed the requirement for PI3K activity and serine phosphorylation by the use of IRS-1 mutants, expressed in LNCaP cells. Serine phosphorylation inhibits IGF-I-induced tyrosyl phosphorylation of IRS-1, which is restored by the expression of wild-type PTEN or by inhibition of PI3K activity. Finally, IRS-1 in LNCaP cells co-immunoprecipitates with integrin alpha 5 beta 1, and the association is again IGF-I-independent. We conclude that in LNCaP cells, IRS-1 is serine phosphorylated by PI3K, generating effects that are different, and even opposite, from those generated by IGF-I.
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PMID:Mechanisms of regulation of cell adhesion and motility by insulin receptor substrate-1 in prostate cancer cells. 1131 80

Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.
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PMID:Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China. 1138 55

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.
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PMID:Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. 1148 52


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