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)

Growth factors and cytokines mediate communication between the epithelial and stromal compartments of the prostate. In prostate cancer (PCa), changes in the spatial arrangements of the two compartments (i.e. basement membrane invasion), DNA mutations, or cellular dedifferentiation (i.e. myofibroblasts) leads to significant changes in gene expression within both compartments. This results in altered cytokine and/or growth factor signaling in PCa. Recently, a stromal-specific androgen receptor (AR) coactivator, Hic-5/ARA55, has been identified that may play a role in regulating expression of the growth factor and/or cytokine expression in the prostate. Specifically, Hic-5/ARA55 expression influences androgen-induced keratinocyte growth factor (KGF) expression in WPMY-1 prostate stromal cells. Because Hic-5/ARA55's expression is also altered in PCa, it may play a role in the differential cellular signaling events that occur during tumor progression.
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PMID:Hic-5/ARA55: a prostate stroma-specific AR coactivator. 1716 36

Transcriptional regulation by the androgen receptor (AR) is critical for male sexual development and prostate cancer. In this study, we used an expression cloning strategy to identify molecules that regulate AR-driven transcription. Screening of a human cDNA library resulted in isolation of caspase-8 (Casp8), an initiator caspase that mediates death-receptor-induced apoptosis. Casp8 repressed AR-dependent gene expression independently of its apoptotic protease activity by disrupting AR amino-terminal and carboxy-terminal (N/C) interaction and inhibiting androgen-induced AR nuclear localization. Protein-protein interaction analysis revealed that three motifs in Casp8 specifically interacted with the motifs that are known to be involved in AR N/C interaction. Substitutions of the amino-acid residues critical for AR-Casp8 interactions abolished the Casp8-mediated inhibition of AR transactivation. In addition, knockdown of Casp8 by RNA interference specifically affected the androgen-dependent expression of AR-targeting genes in LNCaP cells. These results indicate that Casp8 has a novel function beyond its known role in the mediation of apoptosis.
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PMID:A novel function of caspase-8 in the regulation of androgen-receptor-driven gene expression. 1717 Jul 3

The androgen-androgen receptor (AR) system plays vital roles in a wide array of biological processes, including prostate cancer development and progression. Several growth factors, such as insulin-like growth factor 1 (IGF1), can induce AR activation, whereas insulin resistance and hyperinsulinemia are correlated with an elevated incidence of prostate cancer. Here we report that Foxo1, a downstream molecule that becomes phosphorylated and inactivated by phosphatidylinositol 3-kinase/Akt kinase in response to IGF1 or insulin, suppresses ligand-mediated AR transactivation. Foxo1 reduces androgen-induced AR target gene expressions and suppresses the in vitro growth of prostate cancer cells. These inhibitory effects of Foxo1 are attenuated by IGF1 but are enhanced when it is rendered Akt-nonphosphorylatable. Foxo1 interacts directly with the C terminus of AR in a ligand-dependent manner and disrupts ligand-induced AR subnuclear compartmentalization. Foxo1 is recruited by liganded AR to the chromatin of AR target gene promoters, where it interferes with AR-DNA interactions. IGF1 or insulin abolish the Foxo1 occupancy of these promoters. Of interest, a positive feedback circuit working locally in an autocrine/intracrine manner may exist, because liganded AR up-regulates IGF1 receptor expression in prostate cancer cells, presumably resulting in higher IGF1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo1 is a novel corepressor for AR, and IGF1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo1 inhibition. These results highlight the potential involvement of metabolic syndrome and hyperinsulinemia in prostate diseases and further suggest that intervention of IGF1/insulin-phosphatidylinositol 3-kinase-Akt signaling may be of clinical value for prostate diseases.
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PMID:Insulin-like growth factor 1/insulin signaling activates androgen signaling through direct interactions of Foxo1 with androgen receptor. 1720 44

Prostate cancer is a disease involving complicated multiple-gene alterations. Both NKX3.1 and p53 are related to prostate cancer and play crucial roles in prostate cancer progression. However, little is known about the relationships and interactions between p53 and NKX3.1 in prostate cancer. We found that NKX3.1 expression is down-regulated by over-expression of wild type (wt) p53 in prostate cancer LNCaP cells. NKX3.1 is down-regulated at both the mRNA and protein levels by p53 over- expression due to either transient transfection of exogenous p53 or induction of endogenous p53. p53 over-expression represses androgen-induced transactivation of NKX3.1 by inhibiting the promoter of the androgen acceptor (AR) gene and by blocking AR-DNA binding activity. In addition, transfection with the p21 expression vector (pPSA-p21) showed that p21 does not reduce NKX3.1 expression, indicating that NKX3.1 expression is not the result of nonspecific effects of cell growth arrest. Our results provide biochemical and cellular biologic evidence that NKX3.1 is down-regulated by p53 over-expression in prostate cancer cells.
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PMID:p53 overexpression represses androgen-mediated induction of NKX3.1 in a prostate cancer cell line. 1720 38

NDRG1 is known to play important roles in both androgen-induced cell differentiation and inhibition of prostate cancer metastasis. However, the proteins associated with NDRG1 function are not fully enumerated. Using coimmunoprecipitation and mass spectrometry analysis, we identified 58 proteins that interact with NDRG1 in prostate cancer cells. These proteins include nuclear proteins, adhesion molecules, endoplasmic reticulum (ER) chaperons, proteasome subunits, and signaling proteins. Integration of our data with protein-protein interaction data from the Human Proteome Reference Database allowed us to build a comprehensive interactome map of NDRG1. This interactome map consists of several modules such as a nuclear module and a cell membrane module; these modules explain the reported versatile functions of NDRG1. We also determined that serine 330 and threonine 366 of NDRG1 were phosphorylated and demonstrated that the phosphorylation of NDRG1 was prominently mediated by protein kinase A (PKA). Further, we showed that NDRG1 directly binds to beta-catenin and E-cadherin. However, the phosphorylation of NDRG1 did not interrupt the binding of NDRG1 to E-cadherin and beta-catenin. Finally, we showed that the inhibition of NDRG1 expression by RNA interference decreased the ER inducible chaperon GRP94 expression, directly proving that NDRG1 is involved in the ER stress response. Intriguingly, we observed that many members of the NDRG1 interactome are androgen-regulated and that the NDRG1 interactome links to the androgen response network through common interactions with beta-catenin and heat shock protein 90. Therefore we overlaid the transcriptomic expression changes in the NDRG1 interactome in response to androgen treatment and built a dual dynamic picture of the NDRG1 interactome in response to androgen. This interactome map provides the first road map for understanding the functions of NDRG1 in cells and its roles in human diseases, such as prostate cancer, which can progress from androgen-dependent curable stages to androgen-independent incurable stages.
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PMID:Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells. 1722 Apr 78

Although androgen-hypersensitivity is one of the possible pathways of hormone-resistance in prostate cancer, the mechanisms of androgen-hypersensitivity are still largely unknown. Using androgen-hypersensitive prostate cancer cells LN-TR2, established from androgen-sensitive LNCaP cells by the long term treatment with tumor necrosis factor alpha, we explored the mechanisms of androgen-hypersensitivity in prostate cancer cells which may thus play a role in hormone-resistance. We examined the androgen receptor (AR) DNA sequence and the expression levels of AR and 8 AR cofactors in LNCaP and LN-TR2 cells. As a result, no novel mutation was developed in AR DNA in LN-TR2 cells. We observed higher expressions of nuclear AR upon androgen-treatment and 2 AR coactivators, ARA55 and TIF2, in LN-TR2 compared to LNCaP cells. An overexpression of ARA55 or TIF2 enhanced androgen-induced AR transcriptional activity in LNCaP cell. In the presence of those AR coactivators, AR activity was observed even at low concentrations of androgen. In 2 of 6 patients, the expression level of ARA55 was higher in cancer cells in hormone-resistant tumor than those in hormone-sensitive tumor. Taken together, our results suggest that prostate cancer cells change androgen-sensitivity by an overexpression of nuclear AR and AR coactivators, thus, resulting in transition from androgen-dependent to androgen-independent prostate cancer cells. An increase in nuclear AR and AR coactivators may cause androgen-hypersensitivity of prostate cancer cells and thus play a role in hormone-resistance, at least in some patients with prostate cancer.
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PMID:Prostate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; a possible mechanism of hormone-resistance of prostate cancer cells. 1736 55

We compared prostatic proteins in patients operated for adenoma or cancer. 630 protein fractions were obtained from each tissue sample after fractionation by two-dimentional electrophoresis according to O'Farrell. Comparison of the samples from adenoma and cancer showed their difference by 7 proteins among which were isoforms of glyceraldehydes-3-phosphate-dehydrogenase, alpha-collagen and several little known proteins. Most of the cancer patients had the protein with molecular mass 19 kDa and isoelectric point 9.0. By the results of mass-spectrometry this protein was identified as androgen-induced secreted protein AGR2. This protein is considered a potential oncomarker. Prospects of some postgenome technologies for detection of new diagnostic markers of prostatic cancer are discussed.
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PMID:[New approaches to molecular diagnosis of prostatic cancer]. 1744 46

The identification of molecular determinants involved in the promotion of metastasis and development of androgen insensitive prostate cancer (AI-PCa) is necessary to discriminate aggressive from indolent disease and to identify therapeutic targets for advanced disease. Overexpression of one particular member of the insulin like growth factor (IGF) axis, IGFBP-2, is implicated in the development of AI-PCa and other cancers. Using the LNCaP human PCa progression model, we show that the AI and metastatic prostate cancer cell line C4-2B4 expresses greater amounts of secreted IGFBP-2 than the androgen sensitive (AS), non-metastatic LNCaP progenitor cell line. Further, the ability of androgens to decrease extracellular IGFBP-2 levels is attenuated in the AI and metastatic C4-2 cell line. The ability of androgen to negatively regulate extracellular IGFBP-2 levels was blocked by Casodex in a dose-dependent manner. The mechanism underlying the androgen-induced downregulation of secreted IGFBP-2 appears to involve extracellular proteolysis, resulting in the production of IGFBP-2 fragments lacking the ability to bind IGF-I and IGF-II. As C4-2 cells have an attenuated ability to proteolyze IGFBP-2 in response to androgen and C4-2B4 cells express greater amounts of IGFBP-2, our data implies that the diminished regulation of IGFBP-2 and loss of associated proteolytic fragments play a role in the increased metastatic behavior of these cells in vivo. Furthermore, our results suggest that either increased levels of intact IGFBP-2 or decreased levels of IGFBP-2 proteolytic fragments could serve as a biomarker to monitor for progression to AI-PCa.
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PMID:Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model. 1749 83

The anti-androgenic activity of the ethanol extract of the fruiting body of Ganoderma lucidum has been previously reported. Ganoderol B with 5alpha-reductase inhibitory activity and the ability to bind to androgen receptor (AR) can inhibit androgen-induced LNCaP cell growth and suppress regrowth of the ventral prostate induced by testosterone in rats. The down-regulation of AR signaling by ganoderol B provides an important mechanism for its anti-androgenic activity. In view of the fact that PSA (prostatic specific antigen, a well-accepted prognostic indicator of prostate cancer) is down-regulated, an important implication of this study is that ganoderol B intervention strategy aimed at toning down the amplitude of androgen signaling could be helpful in controlling morbidity of prostate cancer. In conclusion, our result suggests that ganoderol B might be useful in prostate cancer and benign prostatic hyperplasia (BPH) therapy through suppressing the function of androgen and its receptor.
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PMID:The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum. 1749 97

Androgens and the androgen receptor (AR) act in cells by modulating gene expression. Through gene microarray studies, we have identified Ets Variant Gene 1 (ETV1) as a novel androgen-regulated gene. Our data demonstrate that ETV1 mRNA and protein are up-regulated in response to ligand-activated AR in androgen-dependent LNCaP cells, but there is no detectable ETV1 expression in normal prostate cells. The ETV1 promoter is induced by androgens and recruits the AR in the context of chromatin. ETV1-regulated endogenous matrix metalloproteinase genes can be induced by ligand-activated AR. In contrast to the hormone-induced expression in androgen-dependent LNCaP cells, ETV1 expression in androgen-independent LNCaP cells is high and unresponsive to androgen. This androgen-independent ETV1 expression contrasts with the hormone-dependent expression observed for TMPRSS2 in these androgen-independent prostate cancer cells. ETV1 is overexpressed in prostate cancer independent of the TMPRSS2:ETV1 translocation. Disruption of ETV1 expression in both androgen-dependent and androgen-independent prostate cancer cells significantly compromises the invasion capacity of these cells, suggesting an important role for ETV1 in prostate cancer metastasis. Collectively, these results demonstrate that ETV1 expression transitions from androgen-induced to androgen-independent as prostate cancer cells switch from hormone-dependent to hormone-refractory and suggest that this transition may be in part responsible for the elevated levels of ETV1 observed in prostate tumors. Additionally, our data provide an indirect mechanism of AR regulation of gene expression, via the transactivation of the transcription factor ETV1.
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PMID:ETV1 is a novel androgen receptor-regulated gene that mediates prostate cancer cell invasion. 1750 60


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