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)

Despite the specificity inferred by its name, glycogen synthase kinase (GSK)-3beta is an important kinase with a plethora of significant cellular targets, including cytoskeletal proteins and transcription factors, and its activity is regulated by phosphorylation on tyrosine/serine residues. As part of our efforts to dissect the molecular basis responsible for androgen-independent progression of prostate cancer, we investigated the role of GSK-3beta in androgen-stimulated gene expression in human prostate cancer cells. Pretreatment of prostate cancer cells harboring wild-type or mutant androgen receptor with the GSK-3beta inhibitors, lithium chloride (LiCl), RO318220, or GF109203X, inhibited R1881-stimulated androgen-responsive reporter activity in a dose- and time-dependent manner. In addition, the expression of two endogenous androgen-stimulated gene products, prostate-specific antigen and matrix metalloproteinase-2, was suppressed by the GSK-3beta inhibitors in those cells. Most importantly, knocking down GSK-3beta expression via a small interference RNA-mediated gene silencing approach also reduced R1881-stimulated gene expression, demonstrating the specificity of GSK-3beta involvement. Moreover, R1881 treatment of the cells increased phosphorylation status of GSK-3beta on tyrosine residue Y(216) but not on serine residue S(9). Pretreatment of the cells with phosphatidylinositol 3-kinase inhibitor LY294002 or wortmannin, which blocks androgen action in cells, abolished R1881-induced GSK-3beta Y(216) phosphorylation. However, the phosphatidylinositol 3kinase or GSK-3beta inhibitors did not block R1881-induced nuclear translocation of androgen receptor. Finally, knocking down the expression of Akt or beta-catenin, the two GSK-3beta-related signaling molecules, via siRNA-mediated gene silencing did not significant affect R1881-stimulated gene expression. These findings suggest that GSK-3beta activity is required for androgen-stimulated gene expression in prostate cancer cells.
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PMID:Glycogen synthase kinase-3beta activity is required for androgen-stimulated gene expression in prostate cancer. 1498 90

Androgen-regulated genes (ARGs) are essential for the development of the prostate. Ironically, ARGs are also responsible for the pathogenesis of prostate cancer. We used oligonucleotide array technology to study the expression profiles of ARGs in LNCaP prostate cancer cells and identified 692 dihydrotestosterone-regulated genes. Representative clusters containing genes with similar expression patterns to prostate-specific antigen and other known ARGs are discussed. Based on functional information, we categorized several candidate targets for prostate cancer therapy and diagnosis. Although many of these candidate targets are known to play an important role in cancer development, several are novel genes to the field of prostate cancer. A cross-comparison study of our results with those that have been previously published from three other array experiments using a similar LNCaP model validated 13 of these candidate targets as androgen-regulated. FKBP51 (FK506-binding immunophilin 51) was found in the same cluster as prostate-specific antigen and its protein expression was increased in LNCaP cells treated with either dihydrotestosterone or synthetic androgen R1881. Results from mining the Gene Logic BioExpress database showed that FKBP51 expression is significantly higher in the prostate cancer group than in the normal and normal adjacent group. Additionally, the androgen-independent prostate tumor xenograft, CWR22R, had higher FKBP51 protein levels than that of the androgen-dependent prostate tumor xenograft, CWR22. A tissue microarray study further revealed that FKBP51 protein expression was higher in prostate cancer specimens than in benign prostate tumor samples. These results suggest the potential value of FKBP51 as a novel diagnostic marker or target for prostate cancer therapy.
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PMID:Identification and validation of novel androgen-regulated genes in prostate cancer. 1513 Oct 19

Many recent evidences indicate that androgen-sensitive prostate cancer cells have a lower malignant phenotype that is in particular characterized by a reduced migration and invasion. We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of alpha6beta4 integrin expression. The treatment with the synthetic androgen R1881 further reduced invasion of the cells without, however, modifying alpha6beta4 expression on the cell surface, suggesting an interference with the invasion process in response to EGF. We investigated whether the presence of the AR could affect EGF receptor (EGFR)-mediated signaling in response to EGF by evaluating autotransphosphorylation of the receptor as well as activation of downstream signalling pathways. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signalling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. An interaction between EGFR and AR has been demonstrated by immunoconfocal and co-immunoprecipitation analysis in PC3-AR cells, suggesting a possible interference of AR on EGFR signalling by interaction of the two proteins. In conclusion, our results suggest that the expression of AR by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signalling in response to EGF leading to invasion through a mechanism involving an interaction between AR and EGFR.
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PMID:The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells. 1528 68

Prostate cancer cells require high rates of de novo fatty acid synthesis and protein synthesis for their rapid growth. We report here that the growth of these cells is markedly diminished by incubation with activators of AMP-activated protein kinase (AMPK), a fuel-sensing enzyme that has been shown to diminish both of these processes in intact tissues. Inhibition of cell growth was observed when AMPK was activated by either 5-aminoimidazole-4-carboxamide riboside (AICAR) or the thiazolidinedione rosiglitazone. Thus, a 90% inhibition of the growth of androgen-independent (DU145, PC3) and androgen-sensitive (LNCaP) cells was achieved after 4 days of exposure to one or both of these agents. Where studied, this was associated with a decrease in the concentration of malonyl CoA, an intermediate of de novo fatty acid synthesis, and an increase in expression of the cell cycle inhibitor p21. In addition, AICAR inhibited two key enzymes involved in protein synthesis, mTOR and p70S6K, and blocked the ability of the androgen R1881 to increase cell growth and the expression of two enzymes for de novo fatty acid synthesis, acetyl CoA carboxylase and fatty acid synthase, in the LNCaP cells. The results suggest that AMPK is a potential target for the treatment of prostate cancer.
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PMID:AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. 1535 29

The androgen receptor co-activator CREB (cAMP-response element binding protein)-binding protein (CBP) enhances androgen receptor activity after stimulation by androgenic hormones and androgen receptor antagonists. The aim of the present study was to investigate the regulation of CBP expression by steroid and peptide hormones in prostate cancer. For this purpose, LNCaP cells were treated with the synthetic androgen methyltrienolone (R1881), epidermal growth factor, insulin-like growth factor-I or interleukin-6 (IL-6). CBP protein and mRNA expression were studied by western blotting and real-time PCR, respectively. CBP expression was also investigated in tissue specimens obtained from 26 patients with therapy-resistant carcinoma of the prostate. In LNCaP cells, CBP protein was down-regulated by R1881 or IL-6. The non-steroidal anti-androgen bicalutamide antagonized the effects of R1881 and the Janus kinase inhibitor AG 490 reversed the effects of IL-6. In contrast, neither R1881 nor IL-6 caused any effect on CBP expression in the PC-3 cell line. In LNCaP cells, the inhibition of CBP expression by R1881 or IL-6 was also observed at the mRNA level. CBP protein was detected in all 26 specimens by immunohistochemistry. The results suggest that up-regulation of CBP during androgen ablation may be relevant to the failure of endocrine therapy in patients with prostate carcinoma.
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PMID:The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer. 1537 87

Elevated circulating interleukin-6 (IL6) and up-regulated S100P in prostate cancer (PCa) specimens correlate independently with progression to androgen-independent and metastatic PCa. The cause of up-regulated S100P levels in advanced PCa remains to be determined. We investigated the possibility that IL6 is an inducer of S100P. Determination of mRNA and protein levels by real-time PCR and Western blotting revealed that IL6 is a more potent inducer of S100P than the synthetic androgen, R1881, in the LNCaP/C4-2B model of PCa progression. IL6 did not require androgen to induce S100P in these cells, which express a functional androgen receptor (AR). Like R1881, IL6 was unable to induce S100P in PC3 cells that lack a functional AR. IL6 did not strongly induce the AR-dependent genes PSA and KLK2 and, contrary to R1881, down-regulated Cyr61/CCN1, a potential marker that is down-regulated in PCa. Epidermal growth factor (EGF), which like IL6 is a non-androgen activator of the AR, did not induce S100P. The data identifies a unique gene-induction profile for IL6 and suggests that IL6 may require a functional AR for S100P induction. A link between elevated IL6 and up-regulated S100P in androgen-refractory and metastatic PCa is postulated.
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PMID:Interleukin-6 is a potent inducer of S100P, which is up-regulated in androgen-refractory and metastatic prostate cancer. 1547 88

The Wnt signaling pathway is aberrantly activated in many tumor types, including those of the prostate, in which beta-catenin accumulates in cell nuclei and acts as a transcriptional coregulator for the androgen receptor. Because activating mutations in the beta-catenin gene are rare in prostate cancer, we have looked for altered expression of other components of the Wnt signaling pathway in prostate cancer cells. Here we determined the expression levels of Wnt family genes in cultured human prostate cells and prostate cancer cell lines. We found that WNT11 expression is elevated in hormone-independent prostate cancer cell lines. Additional analysis indicated that WNT11 expression is also elevated in high-grade prostatic tumors and in hormone-independent xenografts. Growth of hormone-dependent LNCaP cells in hormone-depleted media led to increased WNT11 expression, which was repressed by the synthetic androgen R1881. This repression was inhibited by the antiandrogen bicalutamide, suggesting that androgens negatively regulate WNT11 expression through the androgen receptor. Expression of WNT11 inhibited androgen receptor transcriptional activity and cell growth in androgen-dependent cells but not in androgen-independent cells. WNT11 inhibited activation of the canonical Wnt pathway by WNT3A in HEK 293 cells and inhibited basal beta-catenin/Tcf transcriptional activity in LNCaP cells. However, expression of stabilized beta-catenin did not prevent the inhibition of androgen receptor transcriptional activity by WNT11. Our observations are consistent with a model in which androgen depletion activates WNT11-dependent signals that inhibit androgen-dependent but not androgen-independent cell growth.
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PMID:Analysis of Wnt gene expression in prostate cancer: mutual inhibition by WNT11 and the androgen receptor. 1552 Jan 98

Androgen receptor (AR) recognizes and binds to 15-bp palindromic androgen response element (ARE) sequences with high affinity in vitro, which consist of two hexameric half-sites arranged as inverted repeats with a 3-bp spacer. Although a few near-consensus ARE sequences have been actually identified in the transcriptional regulatory regions of androgen-responsive genes, it has been unclear whether the exact consensus sequences function as bona fide AREs in vivo. A genome-wide in silico screening of palindromic AREs identified 563 exact consensus sequences in the human genome. The distribution of perfect palindromic AREs among the chromosomes is basically consistent with the length of chromosomes. Using human prostate cancer cell line LNCaP treated with a synthetic androgen R1881 as a model, in vivo AR binding abilities of 21 consensus AREs were analyzed by chromatin immunoprecipitation. Of 21 genomic fragments containing perfect AREs in chromosome X, 8 fragments recruited more ARs (>4-fold enrichment) even compared with the proximal ARE region of prostate-specific antigen. A couple of proximal genes or putative transcripts in the vicinity of the perfect AREs were found to be androgen-responsive analyzed by quantitative RT-PCR. Our results suggest that some of perfect palindromic AREs could function as in vivo AR binding sites in the human genome and regulate gene transcription.
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PMID:Identification and functional analysis of consensus androgen response elements in human prostate cancer cells. 1555 70

Recent evidence indicates that androgen-sensitive prostate cancer cells have a less malignant phenotype characterized by reduced migration and invasion. We investigated whether the presence of the androgen receptor could affect EGFR-mediated signaling by evaluating autotransphosphorylation of the receptor as well as activation of the downstream signaling pathway PI3K/AKT. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. Our results suggest that the expression of androgen receptors by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signaling leading to invasion in response to EGF. We used the selective tyrosine kinase inhibitor of the EGFR gefitinib (also known as Iressa or ZD1839) to further investigate the role of EGFR in the invasion and growth of PC cells. We demonstrate that in the androgen-insensitive cell lines PC3 and DU145 this compound was able to decrease in vitro invasion of Matrigel by inhibiting EGFR autotransphosphorylation and subsequent PI3K activation. Gefitinib may be useful in the treatment of androgen-independent prostate cancer to limit not only the proliferation but also the invasion of these tumors.
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PMID:Signaling mechanisms that mediate invasion in prostate cancer cells. 1565 Feb 53

In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an approximately 6-fold increase in IGF-IR expression in androgen receptor (AR)-positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity, because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.
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PMID:Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. 1575 83


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