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)

Perturbations of stromal-epithelial interactions in the developing tumour can contribute to cancer invasion and metastasis. The structurally related metallopeptidases endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP) contribute sequentially to the synthesis and inactivation of ET-1, a mitogenic peptide that has been shown to affect tumour behaviour. This study has investigated the interaction between metastatic tumour epithelial cells, which lack NEP, and stromal cells, which we have shown to express ECE-1 (stromal-epithelial interactions), using Matrigel invasion chambers. The epithelial cell lines utilised in this study include androgen-sensitive LNCaP, androgen-independent PC-3, Du145 and recently established PNT-1a, PNT2-C2 and P4E6 prostate cell lines. Specific inhibition of endogenous ECE-1 activity in stromal cells reduced PC-3 and Du145 invasion by 70 and 50%, respectively. Addition of recombinant NEP to inactivate endogenous mitogenic peptides resulted in 50 and 20% reductions in invasion in PC-3 and Du145 cells, respectively. Neutral endopeptidase effects were reversed in the presence of thiorphan, a specific NEP inhibitor. Supplementation of defined media with bradykinin and ET-1 significantly increased PC-3 invasion by 40 and 50%, respectively. Du145 cell invasion increased by approximately 100% on adding ET-1. These studies implicate the metallopeptidases NEP and ECE-1 as mediators of prostate cancer invasion via a stromal/epithelial interaction.
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PMID:Stromal-epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression. 1508 88

The mechanism by which neurotensin (NT) promotes the growth of prostate cancer epithelial cells is not yet defined. Here, androgen-independent PC3 cells, which express high levels of the type 1 NT-receptor (NTR1), are used to examine the involvement of epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (ERK, SAPK/JNK and p38), PI3 kinase and PKC in the mitogenic effect of NT. NT dose dependently (0.1-30 nM) enhanced phosphorylation of EGFR, ERK and Akt, reaching maximal levels within 3 min as measured by Western blotting. These effects were associated with an accumulation of EGF-like substance(s) in the medium (assayed by EGFR binding) and a 2-fold increase in DNA synthesis (assayed by [3H]thymidine incorporation). The DNA synthesis enhancement by NT was non-additive with that of EGF. The NT-induced stimulation of EGFR/ERK/Akt phosphorylation and DNA synthesis was inhibited by EGFR-tyrosine kinase inhibitors (AG1478, PD153035), metallo-endopeptidase inhibitor phosphoramidon and by heparin, but not by neutralizing anti-EGF antibody. Thus, transactivation of EGFR by NT involved heparin-binding EGF (HB-EGF or amphiregulin) rather than EGF. The effects of NT on EGFR/ERK/Akt activation and DNA synthesis were attenuated by PLC-inhibitor (U73122), PKC-inhibitors (bisindolylmaleimide, staurosporine, rottlerin), MEK inhibitor (U0126) and PI3 kinase inhibitors (wortmannin, LY 294002). We conclude that NT stimulated mitogenesis in PC3 cells by a PKC-dependent ligand-mediated transactivation of EGFR, which led to stimulation of the Raf-MEK-ERK pathway in a PI3 kinase-dependent manner.
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PMID:Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. 1517 34

Cluster designation (CD) antigens are cell surface markers that can be used to identify constituent cell populations of an organ. We have previously determined the CD phenotype of normal prostate parenchymal cells and are now extending this analysis to prostate cancer. Since expression of CD antigens is associated with cellular differentiation, cancer cells may differ from their normal counterpart in their CD profile. Compared with luminal secretory cells, prostate adenocarcinoma cells are frequently negative for CD10 and CD13, express increased levels of the cell activation molecule CD24, and decreased levels of the apoptosis-associated multifunctional enzyme CD38. Expression of CD57, CD63, CD75s, CD107a, CD107b, CD164, and CD166 by cancer cells is similar to that of secretory cells. Prostate basal epithelial cells do not express the CD antigens characteristic of prostate secretory cells; and the basal cell CD markers, CD29, CD44, CD49b, CD49f, CD104, and nerve growth factor receptor (NGFR) are not expressed by cancer cells. The preferential expression of secretory cell-associated CD markers by prostate cancer cells suggests a closer lineage relationship between cancer cells and secretory cells than basal cells. Although the above cancer CD phenotype was the most frequently seen, some prostate cancers contained populations of CD10- and/or CD13-positive cells, and CD57-negative cells. Furthermore, the cancer phenotype of tumor metastasis is different. Despite its low frequency in primary tumors, CD10 is expressed by virtually all of the nodal metastases of prostate cancer. In addition, stromal fibromuscular cells associated with primary prostate cancer differ from stromal cells in benign prostate tissue by an increased level of expression of the cell activation molecule, CD90. In summary, our data show that the CD marker expression profile of prostate cancer cells most closely resembles that of secretory prostate epithelial cells and that some prostate cancers consist of heterogeneous cell populations as distinguished by CD-marker expression profiles.
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PMID:Heterogeneity in primary and metastatic prostate cancer as defined by cell surface CD profile. 1550 25

We have performed whole genome expression profiling of 28 patient prostate tumor samples and 12 normal prostate samples and identified 55 upregulated and 60 downregulated genes significantly changed in prostate tumor samples compared to normal prostate tissues. Among the members of the upregulated gene set was the developmental transcription factor Homeobox C6 (HOXC6). Silencing of HOXC6 expression using small-interfering RNA (siRNA) resulted in decreased proliferation rates for both androgen-dependent LnCaP cells and the LnCaP-derived androgen-independent C4-2 cell line. Flow cytometry and immunoblotting for the caspase-cleaved form of poly-ADP ribose polymerase (PARP) determined that the decrease in cell numbers was due to increased apoptosis. To validate the specificity of the siRNA-induced apoptosis, LnCaP cells were cotransfected with siRNA specific to the HOXC6 3'UTR and a mammalian expression vector containing the HOXC6 open reading frame, but lacking the 3'UTR. Overexpression of HOXC6 rescued the LnCaP cells from HOXC6 siRNA-induced apoptosis, and increased growth of control GFP siRNA-transfected cells. Expression profiling of HOXC6 siRNA transfections and HOXC6 overexpression identified neutral endopeptidase (NEP) and insulin-like growth factor binding protein-3 (IGFBP-3) as potential proapoptotic repression targets of HOXC6. Our data suggest that HOXC6 may be a novel potential therapeutic target for prostate cancer.
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PMID:Loss of HOXC6 expression induces apoptosis in prostate cancer cells. 1563 92

Preclinical studies of prostate cancer (CaP) have employed a genetically engineered mouse model, since there is no naturally occurring CaP in rodents. We have previously reported a new knock-in mouse adenocarcinoma prostate (KIMAP) model. In this study, we demonstrate that the new model possesses a tumor architecture of heterogeneity and multifocality similar to that of human CaP, by utilizing a new compound scoring system to compare with the PSP94 (approved gene symbol Msmb) gene-directed transgenic mouse CaP model (TGMAP). KIMAP mice showed a balanced distribution of tumor extent, which penetrated the prostate gland. Comparative studies on cDNA microarrays demonstrated that KIMAP tumors were upregulated with higher contents of immunoresponse genes, whereas PSP-TGMAP tumors had neuroendocrine (NE) differentiation. The majority of KIMAP mice did not progress to NE CaP, which was observed only at a very late stage and a low frequency. Several tumor marker genes characteristic of human CaP were uniquely identified in KIMAP tumors, including hepsin, maspin, Nkx3.1, CD10 and PSP94 (similar to PSA), etc. The differences between these two CaP models are attributed to the introduction of a single endogenous knock-in mutation. Due to the similarities between human CaP tumors and the PSP-KIMAP tumors, this preclinical model may supplement the current transgenic models to study CaP more accurately.
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PMID:A novel knock-in prostate cancer model demonstrates biology similar to that of human prostate cancer and suitable for preclinical studies. 1572 31

The control of signal peptide activity by cell surface proteases is one of the main factors that regulate the development and behaviour of organisms. In mammals, neprilysins (NEPs) are known to play a key role in these processes and their inactivation can initiate cellular disorganisation, which in turn may lead to prostate cancer or Hirschsprung disease. Although the proteome of the nematode Caenorhabditis elegans has been intensively studied, very little is known about the function of neprilysins. ZK20.6 (NEP-1), the C.elegans protein with highest identity to mammalian neprilysins, is a 753 amino acid residue protein that displays all neprilysin-typical characteristics, including a short intracellular domain, a transmembrane domain and a long extracellular active domain. Here we show that the expression pattern of nep-1 is limited to pharyngeal cells and a single head neuron. Compared to wild-type, the locomotion of nep-1 knockout animals is significantly impaired, a phenotype that can be rescued by the extrachromosomal re-introduction of nep-1. This suggests that this enzyme plays an important role in the regulation of nematode locomotion. Finally, electrophysiological recording of the pharyngeal activity showed a high sensitivity of the nep-1 pharynx to serotonin (5-HT) and to the neuropeptide AF1 (C.elegans FLP-8), indicating that NEP-1 is a central component that controls the neuronal innervation of pharyngeal pumping in C.elegans.
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PMID:Caenorhabditis elegans neprilysin NEP-1: an effector of locomotion and pharyngeal pumping. 1608 Nov 4

Recently, we have reported that inosine 5'-monophosphate dehydrogenase inhibitors, such as mycophenolic acid (MPA), induce the differentiation of PC-3 cells, which are derived from a human androgen-independent prostate cancer, into cells with a phenotype resembling maturing prostate secretory cells. Here, we describe such differentiation induced by the histone deacetylase inhibitor tributyrin. The maturation was defined by cytoplasmic vacuole production and induction of CD10, CD46, CD55, GRP78, keratin 17, and zinc-alpha-2-glycoprotein. To identify additional genes associated with tributyrin-induced PC-3 cell differentiation and to gain some insight into the mechanism that underlies this differentiation, we have, by means of microarray analyses, compared tributyrin-induced gene expression patterns with those of MPA, which initiates PC-3 cell differentiation by a dissimilar mode of action. We suggested that genes induced by both tributyrin and MPA would be most likely associated with differentiation rather than with the unique action of each particular inducer. Our results indicated that tributyrin or MPA induced the expression of a large number of common genes, including genes known or assumed to be NF-kappaB dependent. The NF-kappaB dependency of a group of these genes, which included the PC-3 cell differentiation marker keratin 17, was confirmed by using two common NF-kappaB activation inhibitors, Bay11-082 and TMB-8, and p65 subunit of NF-kappaB complex specific small interfering RNA. Taken together, our results implicate both NF-kappaB-dependent and NF-kappaB-independent genes in the processes leading to PC-3 cell differentiation induced by tributyrin and MPA.
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PMID:Differentiation of androgen-independent prostate cancer PC-3 cells is associated with increased nuclear factor-kappaB activity. 1635 69

Androgen receptor signaling in prostate cancer cells is augmented by the androgen receptor (AR) coactivator p300, which transactivates and acetylates the AR in the presence of dihydrotestosterone (DHT). As prostate cancer (PC) cells progress to androgen independence, AR signaling remains intact, indicating that other factors stimulate AR activities in the absence of androgen. We previously reported that neuropeptide growth factors could transactivate the AR in the presence of very low concentrations of DHT. Here, we examine the involvement of p300 in neuropeptide activation of AR signaling. Transfection of increasing concentrations of p300 in the presence of bombesin into PC-3 cells resulted in a linear increase in AR transactivation, suggesting that p300 acts as a coactivator in neuropeptide-mediated AR transactivation. P300 is endowed with histone acetyltransferase (HAT) activity. Therefore, we examine the effect of bombesin on p300 HAT activity. At 4 h after the addition of bombesin, p300 HAT activity increased 2.0-fold (P<0.01). Incubation with neutral endopeptidase, which degrades bombesin, or bombesin receptor antagonists blocked bombesin-induced p300 HAT activity. To explore the potential signaling pathways involved in bombesin-induced p300 HAT activity, we examined Src and PKCdelta pathways that mediate bombesin signaling. Inhibitors of Src kinase activity or Src kinase siRNA blocked bombesin-induced p300 HAT activity, whereas PKCdelta inhibitors or PKCdelta siRNA significantly increased bombesin-induced p300 HAT activity suggesting that Src kinase and PKCdelta kinase are involved in the regulation of p300 HAT activity. As AR is acetylated in the presence of 100 nM DHT, we next examined whether bombesin-induced p300 HAT activity would result in enhanced AR acetylation. Bombesin-induced AR acetylation at the same motif KLKK observed in DHT-induced acetylation. Elimination of p300 using p300 siRNA reduced AR acetylation, demonstrating that AR acetylation was mediated by p300. AR acetylation results in AR transactivation and the expression of the AR-regulated gene prostate-specific antigen (PSA). Therefore, we examined bombesin-induced AR transactivation and PSA expression in the presence and absence of p300 siRNA and found inhibition of p300 expression reduced bombesin-induced AR transactivation and PSA expression. Together these results demonstrate that bombesin, via Src and PKCdelta signaling pathways, activates p300 HAT activity which leads to enhanced acetylation of AR resulting in increased expression of AR-regulated genes.
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PMID:Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells. 1643 77

An aqueous extract of Epilobium angustifolium and its main compound oenothein B (OeB), a dimeric macrocyclic ellagitannin, are specifically able to induce the neutral endopeptidase (NEP) in prostate cancer cells. The angiotensin-converting enzyme (ACE) is not influenced. Additionally, a weak but statistically significant inhibition of cell proliferation is observed. Simultaneous treatment of the cells with arabinosylcytosine and the extract as well as the OeB, leads to an additional enhancement of NEP activity. Taking into account the role of this peptidase in prostate cancer progression, our results might offer a pharmacological explanation for the use of Epilobium in folk medicine.
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PMID:Induction of neutral endopeptidase activity in PC-3 cells by an aqueous extract of Epilobium angustifolium L. and oenothein B. 1649 33

The neutral endopeptidase (NEP) gene is transcriptionally regulated by androgen in prostate cancer cells. We previously identified in the NEP gene an androgen responsive element (NEP-ARE) and an androgen responsive region (NEP-ARR) that together conveyed only moderate androgen-inducibility [Mol. Cell. Endocrinol. 170 (2000) 131]. Therefore, we characterized the entire genomic structure of the NEP gene and identified ARE1 (ACTCAACAttgTGTCCTTT) and ARE2 (CAGGACAtttTGTCCC), which are located in the 3'-untranslated region and in intron 17, respectively. Steroid-dependent enhancement of transcription was assayed by transfecting the pGL-3-luciferase reporter plasmid containing three copies of ARE1 or ARE2 into PC-3 cells. Luciferase activities were increased 3.6-fold (ARE1) and 5-fold (ARE2) by androgen (AR), 4.2-fold (ARE1) and 8.2-fold (ARE2) by dexamethasone, and 3-fold (ARE1) and 4.1-fold (ARE2) by progesterone. Mutation of the ARE1 and ARE2 sequences completely abrogated androgen-inducibility. We next showed that both ARE1 and ARE2 are involved in the transcriptional regulation of the NEP gene, demonstrating in vitro and in vivo binding with AR as determined by electrophoretic mobility gel shift and chromatin immunoprecipitation (ChIP) assays, Furthermore, ARE1 and ARE2 mediate coordinated androgen-inducibility in both an SV40 promoter and the native NEP type 1 promoter. These data indicate the newly identified ARE1 and ARE2 together with the previously identified NEP-ARE function as androgen response elements, and that androgen regulation of the NEP gene is regulated by the coordinated action of multiple AREs in prostate cancer cells.
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PMID:Multiple androgen response elements cooperate in androgen regulated activity of the type 1 neutral endopeptidase promoter. 1694 32


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