Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostatic secretory and basal or stem cells were isolated from rat ventral prostate lobes by collagenase dispersion and density centrifugation in a Percoll gradient. The membrane-bound adenylyl cyclase of secretory cells could be activated in a dose-dependent manner by vasoactive intestinal peptide (VIP ED50 10(-7)M) but not thyrotropin-releasing hormone (TRH). Conversely, only TRH could significantly stimulate the adenylyl cyclase in basal cell membranes (ED50 5 X 10(-7). In two separate studies enzyme activity was stimulated seven- and 13-fold by this peptide. This action of TRH on prostatic basal cells supports previous reports that high levels of immunologically active TRH have been found in prostate tissue and that TRH stimulates the growth of prostatic cancer cells in vitro.
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PMID:Thyrotropin-releasing hormone (TRH) activates the adenylyl cyclase of nonsecretory cells in the rat ventral prostate. 643 3

The secretion of prostate-specific antigen (PSA) by prostate cancer provides an important tool in the diagnosis and management of this disorder. While androgens are required for PSA synthesis, the neuroendocrine regulation of PSA secretion is less understood. Human prostate is extensively innervated with vasoactive intestinal peptide (VIP)-containing neurons, while both normal and malignant prostate cells contain VIP receptors. Therefore, we investigated the effects of VIP on PSA secretion by LNCaP prostate cancer cells. We found that 1-4-h VIP treatment produces 60-100% increases in PSA secretion by LNCaP cells. Increases in PSA secretion were seen with as little as 10(-10) M VIP with maximum effects at 10(-7) M. The predominant acute effect of VIP was to increase the secretion of stored PSA without increasing PSA mRNA. VIP's effect on PSA secretion involved the production of intracellular cAMP since all doses of VIP which increased secretion were associated with increased cyclic AMP and since dibutyryl-cyclic AMP treatment increased secretion similarly to VIP. These results suggest that VIP regulates PSA secretion by prostate cancer cells and also suggest a role for VIP to regulate PSA secretion by normal prostate epithelial cells.
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PMID:Vasoactive intestinal peptide stimulates prostate-specific antigen secretion by LNCaP prostate cancer cells. 888 83

Radioimaging of various human tumours by means of somatostatin analogues and vasoactive intestinal peptide has been introduced into clinical practice in recent years. The finding that human tumours express various subtypes of somatostatin receptors has led to the development and characterization of a novel peptide tracer, termed MAURITIUS. MAURITIUS identifies a broad range of somatostatin receptors with high binding affinity, and somatostatin receptor 1 with low binding affinity. In order to evaluate patients for tumour radiotherapy with 90Y-MAURITIUS, tumour dose calculation is performed with 111In-MAURITIUS [111In-DOTA-lanreotide]. Treatment is initiated in patients presenting a tumour uptake of > or = 10 Gy/GBq (i.e., standard dose for 1 treatment cycle with 90Y-MAURITIUS). In 25 patients with advanced cancer refractory to conventional antineoplastic treatment 111In-MAURITIUS (approximately 150 MBq; 10 nmol/patient), scintigraphy and dosimetry was performed. Dosimetry data were calculated based on scintigraphic results as well as urine, faeces and blood data. In all patients, at least one tumour site was visualized during the initial few minutes of application. Additional tumour sites not seen on conventional imaging (computerized tomography, magnetic resonance imaging bone scan) could be detected in 6 patients with carcinoids, one patient with prostate cancer and one patient with lymphoma. Liver metastases were visualized in all patients with gastrointestinal cancers, while the primary tumour was not detected in 2 patients with pancreatic, and in 1 patient with rectal, cancer. The calculated radiation dose for tumours and/or metastases ranged between 3-60 Gy/GBq for 90Y-MAURITIUS. MAURITIUS is a universal receptor ligand for a large variety of different human tumours, and is suitable for treatment when labelled with 90Y.
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PMID:"MAURITIUS": tumour dose in patients with advanced carcinoma. 1060 37

Antagonists of GH-releasing hormone (GHRH) and vasoactive intestinal peptide (VIP) inhibit the proliferation of various tumors in vitro and in vivo, but a comparison of their antitumor effects and mechanisms of action has not been reported to date. We recently synthesized and characterized a series of analogs, some of which are primarily GHRH antagonists (JV-1-36, JV-1-38, and JV-1-42), whereas others are more selective for VIP receptors (VPAC-R; JV-1-50, JV-1-51, JV-1-52, and JV-1-53). LNCaP human prostatic cancer cells express VPAC-R, with predominant subtype 1 determined by RT-PCR. Our studies show that GHRH antagonists significantly inhibit the proliferation of both VPAC-R positive LNCaP cells (P < 0.001) and VPAC-R negative MiaPaCa-2 human pancreatic cancer cells cultured in vitro (P < 0.05 to P < 0.001). Growth inhibition of LNCaP cells is accompanied by a proportional reduction in prostate-specific antigen (PSA) secretion (P < 0.001). In a superfusion system, the inhibitory activities of the analogs on the rate of VIP and GHRH-induced PSA secretion correlate well with their VPAC-R binding affinities to LNCaP cell membranes. Antagonists more selective for VPAC-R display a stronger inhibition of inducible PSA release than GHRH antagonists, but have smaller effects or no effects on proliferation and PSA secretion in culture. Collectively, our findings demonstrate that the antiproliferative activity of the analogs on cancer cells is not correlated to their VPAC-R antagonistic potencies. Because GHRH antagonists inhibit the proliferation of LNCaP cells more powerfully than VPAC-R antagonists and also suppress the growth ofVPAC-R-negative MiaPaCa-2 cells, it can be concluded that their antiproliferative effect is exerted through a mechanism independent of VPAC-R.
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PMID:Antagonists of growth hormone-releasing hormone and vasoactive intestinal peptide inhibit tumor proliferation by different mechanisms: evidence from in vitro studies on human prostatic and pancreatic cancers. 1083 Feb 99

The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 with a major role for VPAC1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.
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PMID:Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors. 1172 28

We established a clonal DU-145 prostate cancer cell line (DU-145/AR) stably transfected with androgen receptor (AR) cDNA and investigated the expression of type 1 vasoactive intestinal peptide (VIP) receptor (VIP1R) and type 2 VIP receptor (VIP2R) mRNA in these cells by reverse transcriptase-polymerase chain reaction analysis and the effect of VIP on the invasion and the haptotactic migration of these cells. DU-145/AR cells constitutively expressed both VIP1R and VIP2R mRNA, but the parent DU-145 cells did not. VIP increased the invasive capacity of DU-145/AR cells. VIP also enhanced the haptotactic migration of these cells to fibronectin. However, the growth of these tumor cells was not affected by VIP at any concentrations used in this study. These results indicate that VIP may play a role in the regulation of the invasion of prostate cancer.
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PMID:Vasoactive intestinal peptide (VIP) enhances the cell motility of androgen receptor-transfected DU-145 prostate cancer cells (DU-145/AR). 1179 Apr 58

Elevations of intracellular cAMP in human prostate cancer cells have been shown to increase invasiveness and to promote neuronal differentiation. Since neuroendocrine peptides capable of activating adenyl cyclase are present in prostatic nerves and epithelial neuroendocrine cells, we investigated normal and malignant human prostate cells for changes in intracellular cAMP in response to the prostatic peptides vasoactive intestinal peptide (VIP), calcitonin (CT), and calcitonin gene-related peptide (CGRP). Normal prostate epithelial cells and LNCaP prostate cancer cells exhibited, respectively, 6- and 30-fold increases in intracellular cAMP in response to VIP. ALVA-31 and PPC-1 prostate cancer cells demonstrated 20- to 200-fold increases in cAMP in response to CGRP, while normal epithelial cells and LNCaP cells exhibited smaller (2- to 6-fold) responses. Only DU-145 cells increased cAMP substantially in response to CT. VIP receptor mRNA was identified by Northern blot analysis only in those cells that responded to VIP. CT receptor mRNA was identified only in DU-145 cells by polymerase chain reaction and Southern blot analysis. These results suggest that VIP and possibly CGRP receptors are likely to be present in both normal and malignant prostate cells. VIP or CGRP may regulate secretion of proteases by normal or prostate cancer cells and may influence epithelial cell differentiation.
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PMID:Neuroendocrine peptides stimulate adenyl cyclase in normal and malignant prostate cells. 1250 13

1. In the present study, we describe the expression of the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as well as their receptors in PC-3 cells, a human prostate cancer cell line. In addition, we have investigated their role in apoptosis induced by serum starvation. 2. By RT-PCR and immunocytochemistry assays, we have demonstrated the production of VIP and PACAP in PC-3 cells. 3. We have demonstrated by RT-PCR and binding assays the expression of common PACAP/VIP (VPAC(1) and VPAC(2)) receptors, but not PACAP-specific (PAC(1)) receptors. The pharmacological profile of [(125)I]-VIP binding assays was as follows: VPAC(1) antagonist=VPAC(1) agonist>VIP>VPAC(2) agonist (IC(50)=1.2, 1.5, 2.3 and 30 nM, respectively). In addition, both receptor subtypes are functional since VIP, PACAP-27 or VPAC(1) and VPAC(2) agonists all increased the intracellular levels of cAMP. 4. The expression of both peptides and their receptors is similar in serum-cultured and serum-deprived PC-3 cells. The treatment of serum-deprived PC-3 cells with exogenous VIP or PACAP-27 increases cell number and viability in a dose-dependent manner, as demonstrated by cellular counting and MTT assays. The increased cell survival is exerted through the VPAC(1) receptor, since a VPAC(1), but not VPAC(2), receptor agonist, mimics the effects and a VPAC(1) receptor antagonist blocks it. Moreover, VIP and PACAP-27 inhibit genomic DNA fragmentation in PC-3 cells triggered by serum starvation, and increase the immunoreactivity of the antiapoptotic protein bcl-2. 5. Our results suggest that VIP and PACAP are autocrine/paracrine factors that protect PC-3 cells from apoptosis through VPAC1 receptors.
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PMID:VIP and PACAP are autocrine factors that protect the androgen-independent prostate cancer cell line PC-3 from apoptosis induced by serum withdrawal. 1283 80

Vascular endothelial growth factor (VEGF) is a main factor promoting neovascularization (angiogenesis) of solid tumours as prostate carcinoma. Hypoxia stimulates VEGF gene expression by activating the hypoxia-inducible factor-1 (HIF-1alpha). In the present study, the hypoxia-mimicking agent Ni(2+) induced vasoactive intestinal peptide (VIP) expression at both mRNA and peptide levels but it did not modify the expression of VIP receptors (VPAC(1), VPAC(2) and PAC(1) receptors) in androgen-dependent human LNCaP prostate cancer cells. VIP increased the mRNA levels of VPAC(1) and PAC(1) receptors whereas it decreased VPAC(2) receptor mRNA level. These features support that hypoxia up-regulation of VIP gene expression in prostatic carcinoma may lead to VIP regulation of the expression of its receptors by means of autocrine/paracrine mechanisms. Either VIP or hypoxia mimetics with Ni(2+) increased VEGF expression whereas both conditions together resulted in an additive response. It suggests two independent mechanisms for the observed pro-angiogenic activities of VIP and hypoxia. VIP did not stimulate HIF-1alpha mRNA expression but increased the translocation of HIF-1alpha from the cytosolic compartment to the cell nucleus. Moreover, VIP was unable to modify the expression of the HIF-1alpha inhibitor FIH-1 discarding the possibility of an indirect effect of VIP on HIF-1 transactivation.
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PMID:Hypoxia regulation of expression and angiogenic effects of vasoactive intestinal peptide (VIP) and VIP receptors in LNCaP prostate cancer cells. 1656 10

The effect of vasoactive intestinal peptide (VIP) on cyclooxygenase-2 (COX-2) expression was analyzed in human prostate non-neoplastic (RWPE-1) as well as cancer androgen-dependent (LNCaP) and independent (PC3) cells. The three cell lines expressed VIP mRNA and VIP peptide, as measured by RT-PCR and immunochemistry, which supports an autocrine/paracrine action of VIP in the prostate gland. VIP levels were progressively higher from non-neoplastic to androgen-dependent and independent cells. Real-time RT-PCR and Western-blotting showed that VIP stimulated both COX-2 mRNA and protein expression in a faster manner as prostate cancer stage progressed (i.e. RWPE1<LNCaP<PC3 cells). Furthermore, VIP induced higher levels of COX-2 protein expression in cancer cells as compared with non-neoplastic cells. The anti-inflammatory agent curcumin blocked VIP-induced COX-2 expression in all cell lines studied supporting the involvement of nuclear factor-kappaB (NFkappaB) in such a response. In fact, VIP increased the translocation of the NFkappaB p50 subunit to the nucleus and the binding of the active form to its target gene promoter, as measured by Western-blotting and ELISA, respectively. VIP provoked faster responses according to the most aggressive status in cancer progression (androgen-independent situation). These results together with the existence of two NFkappaB sites in the COX-2 gene promoter together suggest that COX-2 may be a target for VIP in prostate cancer progression. On the other hand, VIP could be a proinflammatory cytokine acting through the NFkappaB/COX-2 system.
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PMID:Vasoactive intestinal peptide induces cyclooxygenase-2 expression through nuclear factor-kappaB in human prostate cell lines Differential time-dependent responses in cancer progression. 1743 57


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