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 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

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58

Neutral endopeptidase 24.11 (NEP) is a 90-110 kDa cell surface cell surface peptidase that is normally expressed by numerous tissues, including prostate, kidney, intestine, endometrium, adrenal glands and lung. This enzyme cleaves peptide bonds on the amino side of hydrophobic amino acids and inactivates a variety of physiologically active peptides, including atrial natriuretic factor, substance P, bradykinin, oxytocin, Leu- and Met-enkephalins, neurotensin, bombesin, endothelin-1, and bombesin-like peptides. NEP reduces the local concentration of peptide available for receptor binding and signal transduction. Loss or decreases in NEP expression have been reported in a variety of malignancies. Reduced NEP may promote peptide-mediated proliferation by allowing accumulation of higher peptide concentrations at the cell surface, and facilitate the development or progression of neoplasia. We have used prostate cancer as model in which to study the involvement of NEP in malignancy. Using a variety of experimental approaches, including recombinant NEP, cell lines expressing wild-type and mutant NEP protein, and cell lines expressing NEP protein with a mutated cytoplasmic domain, we have examined the effects of NEP on cell migration and cell survival. We have shown that the effects of NEP are mediated by its ability to catalytically inactivate substrates such as bombesin and endothelin-1, but also through direct protein-protein interaction with other protein such as Lyn kinase [which associates with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) resulting in NEP-Lyn-PI3-K protein complex], ezrin/radixin/moesin (ERM) proteins, and the PTEN tumor suppressor protein. We review the mechanisms of NEP's tumor suppressive action and how NEP loss contributes to tumor progression.
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PMID:Involvement of neutral endopeptidase in neoplastic progression. 1605 17

Dietary fats, which increase the risk of prostate cancer, stimulate release of intestinal neurotensin (NT), a growth-promoting peptide that enhances the formation of arachidonic acid metabolites in animal blood. This led us to use PC3 cells to examine the involvement of lipoxygenase (LOX) and cyclooxygenase (COX) in the growth effects of NT, including activation of EGF receptor (EGFR) and downstream kinases (ERK, AKT), and stimulation of DNA synthesis. NT and EGF enhanced [3H]-AA release, which was diminished by inhibitors of PLA2 (quinacrine), EGFR (AG1478) and MEK (U0126). NT and EGF phosphorylated EGFR, ERK and AKT, and stimulated DNA synthesis. These effects were diminished by PLA2 inhibitor (quinacrine), general LOX inhibitors (NDGA, ETYA), 5-LOX inhibitors (Rev 5901, AA861), 12-LOX inhibitor (baicalein) and FLAP inhibitor (MK886), while COX inhibitor (indomethacin) was without effect. Cells treated with NT and EGF showed an increase in 5-HETE levels by HPLC. PKC inhibitor (bisindolylmaleimide) blocked the stimulatory effects of NT, EGF and 5-HETE on DNA synthesis. We propose that 5-LOX activity is required for NT to stimulate growth via EGFR and its downstream kinases. The mechanism may involve an effect of 5-HETE on PKC, which is known to facilitate MEK-ERK activation. NT may enhance 5-HETE formation by Ca2+-mediated and ERK-mediated activation of DAG lipase and cPLA2. NT also upregulates cPLA2 and 5-LOX protein expression. Thus, the growth effects of NT and EGF involve a feed-forward system that requires cooperative interactions of the 5-LOX, ERK and AKT pathways.
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PMID:Involvement of arachidonic acid metabolism and EGF receptor in neurotensin-induced prostate cancer PC3 cell growth. 1633 Jan 12

Neurotensin (NT) elevates leukotriene levels in animals and stimulates 5-HETE formation in prostate cancer PC3 cells. PC3 cell growth is stimulated by NT and inhibited by lipoxygenase (LOX) blockers. This led us to test LOX blockers (NDGA, MK886, ETYA, Rev5901, AA861 and others) for effects on NT binding and signaling. LOX blockers dramatically enhanced 125I-neurotensin binding to NT receptor NTR1 in PC3 cells, whereas they inhibited NT-induced inositol phosphate formation. These effects were indirect (binding to isolated membranes was unaffected), receptor-specific (binding to beta2-adrenergic, V1a-vasopressin, EGF and bombesin receptor was unaffected) and pathway-specific (cyclooxygenase inhibitors were inactive). NT receptor affinity was increased but receptor number and % internalization were unchanged. Also supporting the involvement of arachidonic acid metabolism in NTR1 regulation was the finding that inhibitors of PLA2 and DAG lipase enhanced NT binding. These findings suggest that NTR1 is regulated by specific feedback mechanism(s) involving lipid peroxidation and/or LOX-dependent processes.
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PMID:Regulation of neurotensin receptor function by the arachidonic acid-lipoxygenase pathway in prostate cancer PC3 cells. 1640 49

Neuroendocrine (NE) cells are the minor cell populations in normal prostate epithelial compartments. During prostate carcinogenesis, the number of NE cells in malignant lesions increases, correlating with its tumorigenicity and hormone-refractory growth. It is thus proposed that cancerous NE cells promote prostate cancer (PCa) cell progression and its androgen-independent proliferation, although the origin of the cancerous NE cells is not clear. To investigate the role of cancerous NE cells in prostate carcinogenesis, we characterized three NE subclone cell lines-NE-1.3, NE-1.8 and NE-1.9, which were transdifferentiated from androgen-sensitive human PCa LNCaP cells by culturing in an androgen-depleted environment, resembling clinical androgen-ablation therapy. These subclone cells acquire many features of NE cells seen in clinical prostate carcinomas, for example exhibiting a neuronal morphology and expressing multiple NE markers, including neuron-specific enolase, chromogranin B, neurotensin, parathyroid hormone-related peptide, and to a lesser degree for chromogranin A, while lacking androgen receptor (AR) or prostate specific antigen (PSA) expression. These cells represent terminally differentiated stable cells because after 3 months of re-culturing in a medium containing androgenic activity, they still retained the NE phenotype and expressed NE markers. Despite these NE cells having a slow growth rate, they readily developed xenograft tumors. Furthermore, media conditioned by these NE cells exhibited a stimulatory effect on proliferation and PSA secretion by LNCaP cells in androgen-deprived conditions. Additionally, we found that receptor protein tyrosine phosphatase alpha plays a role in upregulating multiple NE markers and acquiring the NE phenotype. These NE cells thus represent cancerous NE cells and could serve as a useful cell model system for investigating the role of cancerous NE cells in hormone-refractory proliferation of PCa cells.
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PMID:Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. 1660 Dec 85

Neuroendocrine (NE)-like cells are hypothesized to contribute to the progression of prostate cancer by producing factors that enhance the growth, survival or metastatic capabilities of surrounding tumor cells. Many of the factors known to be secreted by NE-like cells, such as neurotensin (NT), parathyroid hormone-related peptide, serotonin, bombesin, etc., are agonists for G-protein-coupled receptors, but the signaling pathways activated by these agonists in prostate tumor cells are not fully defined. Identification of such pathways could provide insights into novel methods of treating late-stage disease. Using conditioned culture medium (CM) from LNCaP-derived NE-like cells (as a source of these agonists) or NT (a prototypical component of CM) to treat PC3 cells, we found that the epidermal growth factor (EGF) receptor (EGFR) was transactivated and that such activation was required for maximal PC3 cell mitogenesis, as measured by 5-bromo-2'-deoxy-uridine incorporation or cell number. NT also induced a time-dependent increase in EGFR Tyr(845) phosphorylation and phosphorylation of c-Src and signal transducer and activator of transcription 5b (Stat5b) (a downstream effector of Tyr(845)), events that were blocked by specific inhibition of c-Src (which mediates Tyr(845) phosphorylation of EGFR) or of EGFR. Introduction of mutant forms of EGFR (Tyr(845)) or Stat5b in PC3 cells, or treatment with selective, catalytic inhibitors of EGFR, c-Src and matrix metalloproteinases (MMPs) resulted in the loss of NT-induced stimulation of DNA synthesis, relative to wild-type controls. These data indicate that the mitogenic effect of NT on prostate cancer cells requires transactivation of the EGFR by MMPs and a novel downstream pathway involving c-Src, phosphorylation of EGFR Tyr(845) and activation of Stat5b.
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PMID:Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. 1686 79

Neurotensin (NT) stimulates the proliferation of prostate cancer PC3 cells, which express high levels of its G protein-coupled receptor NTS1. To shed light on mechanisms that might serve to coordinate mitogenic responses to metabolic status, we studied the effects of metabolic inhibitors on NTS1 function. We also related these effects to cellular ATP levels and to the activation of AMP-activated protein kinase (AMPK). Glycolytic and mitochondrial inhibitors, at concentrations that reduced cellular ATP levels, altered NT binding to the cells, inhibited NT-induced inositol phosphate formation, and inhibited NT-induced DNA synthesis. For eight of the nine inhibitors, the potencies to alter NT receptor function correlated to the potencies to decrease cellular ATP levels. In keeping with its known role to oppose metabolic stress, AMPK was activated by the metabolic inhibitors. Accordingly, the AMPK activator AICAR elevated cellular ATP levels and produced effects on NTS1 function that were opposite to those for the metabolic inhibitors. These results indicate that metabolic stress inhibited NTS1 function by a mechanism that involved a fall in cellular ATP levels and that was opposed by activation of AMPK. In a broader context, these findings are compatible with the idea that one means by which cells might coordinate mitogenic signaling to metabolic status could involve changes in growth factor receptor function.
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PMID:Neurotensin receptor binding and neurotensin-induced growth signaling in prostate cancer PC3 cells are sensitive to metabolic stress. 1728 70

Prostate cancer PC3 cells expressed constitutive protein kinase C (PKC) activity that under basal conditions suppressed neurotensin (NT) receptor function. The endogenous PKC activity, assessed using a cell-based PKC substrate phosphorylation assay, was diminished by PKC inhibitors and enhanced by phorbol myristic acid (PMA). Accordingly, PKC inhibitors (staurosporine, Go-6976, Go-6983, Ro-318220, BIS-1, chelerythrine, rottlerin, quercetin) enhanced NT receptor binding and NT-induced inositol phosphate (IP) formation. In contrast, PMA inhibited these functions. The cells expressed conventional PKCs (alpha, betaI) and novel PKCs (delta, epsilon), and the effects of PKC inhibitors on NT binding were blocked by PKC downregulation. The inhibition of NT binding by PMA was enhanced by okadaic acid and blocked by PKC inhibitors. However, when some PKC inhibitors (rottlerin, BIS-1, Ro-318220, Go-69830, quercetin) were used at higher concentrations (>2 microM), they had a different effect characterized by a dramatic increase in NT binding and an inhibition of NT-induced IP formation. The specificity of the agents implicated novel PKCs in this response and indeed, the inhibition of NT-induced IP formation was reproduced by PKCdelta or PKCepsilon knockdown. The inhibition of IP formation appeared to be specific to NT since it was not observed in response to bombesin. Scatchard analyses indicated that the PKC-directed agents modulated NT receptor affinity, not receptor number or receptor internalization. These findings suggest that PKC participates in heterologous regulation of NT receptor function by two mechanisms: a)-- conventional PKCs inhibit NT receptor binding and signaling; and b)-- novel PKCs maintain the ability of NT to stimulate PLC. Since NT can activate PKC upon binding to its receptor, it is possible that NT receptor is also subject to homologous regulation by PKC.
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PMID:Protein kinase C inhibitors alter neurotensin receptor binding and function in prostate cancer PC3 cells. 1831 72

Neurotensin is a neuroendocrine peptide acting as a trophic factor in a variety of cells in vivo but it can also function as an autocrine growth factor in human prostate cancer cells in vitro. In addition, the high-affinity G protein-coupled NT receptor (NTS1) is overexpressed in prostate cancer cell lines. Increasing evidence argues for a direct correlation between specific alternative splice variants and cancer. We detected four splice variants of the NTS1 receptor in human prostate cancer cell lines. These isoforms include one or more exons skipping as well as an alternative 5' splice donor site and are expressed in the late-stage androgen independent prostate cancer cell lines PC3 and DU145, but not in the early-stage androgen-sensitive LNCaP or in normal prostate tissue, which only express the normal transcript. This result shows new splice variants of NTS1 for the first time. The differential expression observed among prostate cancer cell lines and normal prostate tissue opens the interesting possibility of a new role of NT/NTS1 pathway in prostate cancer.
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PMID:Differential expression of new splice variants of the neurotensin receptor 1 gene in human prostate cancer cell lines. 2001 19


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