Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17 beta-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifen's inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.
 ...
PMID:Estradiol augments while tamoxifen inhibits rat mast cell secretion. 138 69

Inositol lipid hydrolysis was monitored in the human breast cancer cell line MCF-7 in response to various bombesin (BN) and substance P (SP) analogues. Both members of the BN family of peptides, i.e. BN and gastrin-releasing peptide (GRP), stimulated a dose-related increase in total inositol phosphate production, with a similar half-maximal effective dose (ED50) around 1 nM. The BN receptor antagonist [Leu13-psi-CH2NH-Leu14]-BN (LLBN) at 1 microM was devoid of agonist activity and displaced the BN dose-response to the right, resulting in a tenfold increase in the ED50 for BN. BN also stimulated a dose-related increase in 45Ca2+ efflux which was also inhibited by LLBN. Two SP analogues [DArg1,D-Pro2,D-Trp7,9,Leu11]-SP and [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-SP ([APheTL]-SP), both antagonized BN-stimulated inositol lipid hydrolysis. [APheTL]-SP (60 and 80 microM) alone also exhibited considerable agonist activity which was not antagonized by LLBN. Indeed, a sub-threshold dose of [APheTL]-SP (40 microM) in the presence of LLBN (10 microM) potentiated the inositol lipid hydrolysis response. BN, GRP, LLBN and [APheTL]-SP all inhibited binding of 125I-labelled GRP to MCF-7 cells, to 50% of that occurring in the absence of the peptides, at concentrations of 150 pM, 150 pM, 150 nM and 600 nM respectively. These data are consistent with the presence of separate but interacting receptors or binding sites for BN and SP analogues, which are coupled to a common signal transduction pathway in human breast cancer cells.
 ...
PMID:Modulation of inositol lipid hydrolysis in human breast cancer cells by two classes of bombesin antagonist. 170 28

Mast cells and histamine-mediated reactions may be altered in patients with cancer. In an attempt to characterize the possible skin defects in patients with cancer, we tested 22 patients suffering from lung cancers, 30 from breast cancers, and 30 age-matched normal individuals, using several compounds, in investigating the pathophysiology of the skin response. Histamine hydrochloride (10 and 100 mg/ml) and codeine phosphate (9%) were tested by prick test. Substance P (50 and 500 ng per injection site), phentolamine (20 micrograms per injection site), and carbachol (1 microgram per injection site) were tested by intradermal skin tests. Skin mast cells were also microscopically examined in 10 patients with lung cancer, five with breast cancer, and 10 normal subjects. The mean wheal sizes induced by all the tested substances were similar in patients with cancer and chronic bronchitis and in normal individuals. The flare to histamine, codeine phosphate, and substance P was completely abolished in 7/22 patients with lung cancer, but the lack of flare was not related to the age of the patients, nor to the staging of cancer, nor to metastasis. The mean numbers of alcian blue-stained or toluidine blue-stained positive mast cells were similar in normal subjects and in subjects with cancer. This study does not confirm the skin hyporeactivity of patients with cancer.
 ...
PMID:Skin test reactivity in patients suffering from lung and breast cancer. 171 Jun 31

Small cell lung cancers (SCLC) and some non-small cell lung cancers (NSCLC) have neuroendocrine features which include production of a variety of neuropeptides, cell surface expression of the receptors for these peptides, and autocrine stimulation by the peptides. Previous studies showed that some peptide antagonists and anti-peptide antibodies inhibited the growth of SCLC cell lines which expressed receptors for the specific peptide. We and others showed that the heterogeneity of peptide receptor expression and responsiveness was a major potential obstacle for developing therapeutic uses of peptide antagonists. In this manuscript we evaluated the effects of 11 peptide antagonists (3 bombesin-specific, 2 cholecystokinin-specific, 1 arginine vasopressin (AVP)-specific, and 5 substance P derivatives with broad specificity) on peptide-induced calcium mobilization and growth of SCLC and NSCLC cell lines. For each antagonist, we determined the dose-response effects, specificity of peptide antagonism, and biological stability in serum using Indo-1AM-based flow cytometric assays. We found that the three bombesin antagonists, S30, SC196, and L336,175, varied in potency from 10 nM to 10 microM, varied in serum stability from 6 h to more than 24 h, and had no effect on the calcium response elicited by other peptides. None of these compounds effectively inhibited the growth of SCLC cell lines in [3H]dThd and cell growth assays in vitro. Similarly, the three cholecystokinin and AVP antagonists were highly specific for cholecystokinin and AVP, respectively, had widely varying potency, but had little inhibitory effect on SCLC growth in vitro. In contrast, the five substance P derivatives inhibited the calcium response to bombesin, AVP, bradykinin, and fetal bovine serum. None of these five antagonists were as potent as the six specific antagonists described above, but they were more effective in inhibiting the growth of SCLC cell lines in vitro. These substance P derivatives inhibited the growth of peptide-sensitive SCLC cell lines more efficiently than their inhibition of peptide-insensitive NSCLC or breast cancer cell lines. Relatively high concentrations of these substance P derivatives were required to inhibit in vitro growth, even in the absence of added peptide. It is likely that more potent broad spectrum antagonists, toxins, or radiolabeled stable antagonists will need to be developed for maximal clinical development of this type of anti-growth factor therapy.
 ...
PMID:Effects of neuropeptide analogues on calcium flux and proliferation in lung cancer cell lines. 751 22

Previously, we have observed that the expression of the neuropeptides bombesin (BN-), the mammalian counterpart being gastrin-releasing peptide (GRP), and substance P (SP) in intact normal tissues, such as salivary and laryngeal glands, increases in response to irradiation. In the present study, the aim was to evaluate whether irradiation can have effects on individual cells that normally synthesize neuropeptides. In addition, since these neuropeptides are potentially mitogenic, we studied tumor cells. Therefore, the estrogen receptor-negative human breast cancer cell line MDA-MB-231 and its subline, with acquired doxorubicin resistance, MDA-MB-231 Dox were examined before irradiation and 4, 10, and 15 days after irradiation with 4 Gy (195 kV, 2 Gy fractions with 4 hours interval). Potential dose related changes were studied by delivering single doses of 2 or 9 Gy with the same technique. Immunohistochemical and radioimmunoassay (RIA) methods were used for detection of the SP and BN/GRP. Before, and at all time points following irradiation, a subpopulation in both cell lines displayed an intense immunostaining of SP and BN/GRP. A partial reorganization of the immunoreactive material was observed 10 days after irradiation. The RIA-analyses displayed signs of a dose-related increase, and a time-dependent transient and significant increase in the content of both peptides. The pattern of changes differed between the two peptides, and was especially pronounced in the doxorubicin resistant cells with regard to SP. Another neuropeptide, calcitonin gene related peptide (CGRP), was not detected in the cells used. The results suggest that irradiation has effects on a population of cultured neuropeptide-synthesizing cells. The occurrence and the specific changes obtained in the levels of neuropeptides, in response to irradiation, might imply an importance in the growth of breast cancer cells and in explaining repair processes following irradiation.
 ...
PMID:Enhanced expression of neuropeptides in human breast cancer cell lines following irradiation. 949 54

Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.
Breast Cancer Res Treat 2003 Jul
PMID:Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. 1288 99

Breast cancer cells (BCCs) have preference for the bone marrow (BM). This study used an in vitro coculture of BCCs and BM stroma to represent a model of early breast cancer metastasis to the BM. The overarching hypothesis states that once BCCs are in the BM, microenvironmental factors induce changes in the expression of genes for cytokines and preprotachykinin-I (PPT-I) in both BCCs and stromal cells. Consequently, the expression of both PPT-I and cytokines are altered to facilitate BCC integration within BM stroma. Cytokine and transcription factor arrays strongly suggested that transforming growth factor-beta (TGF-beta) and c-myc regulate the expression of PPT-I so as to facilitate BCC integration among stroma. Northern analyses and TGF-beta bioassays showed that stromal cells and BCCs influence the level of PPT-I and TGF-beta in each other. In cocultures, PPT-I and TGF-beta expressions were significantly (P < 0.05) increased and decreased, respectively. TGF-beta and PPT-I were undetectable in separate stromal cultures but were expressed as cocultures. Two consensus sequences for c-myc in the 5' flanking region of the PPT-I gene were shown to be functional using gel shift and reporter gene assays. Mutagenesis of c-myc sites, neutralization studies with anti-TGF-beta, and transient tranfections all showed that c-myc is required for TGF-beta-mediated induction of PPT-I in BCCs. TGF-beta was less efficient as a mediator of BCC integration within stroma for c-myc-BCCs. Because the model used in this study represents BCC integration within BM stroma, these studies suggest that TGF-beta is important to the regulation of PPT-I in the early events of bone invasion by BCCs.
 ...
PMID:Bone marrow stroma influences transforming growth factor-beta production in breast cancer cells to regulate c-myc activation of the preprotachykinin-I gene in breast cancer cells. 1534 22

Breast cancer remains the cancer with the highest mortality among women in the United States. Peptides derived from the oncogenic Tac1 gene (full transcript: betaPPT-A) stimulate the proliferation of breast cancer cells (BCCs) via seven-transmembrane G protein-coupled neurokinin 1 (NK1) and NK2 receptors. The NK1 gene could generate full-length (NK1-FL) and truncated (NK1-Tr) transcripts. NK1-Tr lacks 100 residues in their cytoplasmic end, could couple to G proteins, and shows reduced efficiency with respect to internalization and desensitization. This study reports on a role of NK1-Tr in the transformation of nontumorigenic breast cells, and investigates whether Tac1 expression is linked to the generation of NK1-Tr. Western blots and Northern analyses showed coexpressions of NK1-Tr and NK1-FL in BCCs (cell lines and primary cells from patients with different stages of breast cancer). Stable transfections of betaPPT-A or NK1-Tr expression vectors in nontumorigenic cells showed each induces the expression of the other, consequently resulting in a transformed phenotype. Analyses with microarrays indicate similar patterns of cytokine production by NK1-Tr transfectants and BCCs, but not NK1-FL transfectants. These observations indicate tumor-promoting properties by NK1-Tr, but not NK1-FL. Overall, the oncogenic property of Tac1 in breast cells involves concomitant expression of NK1-Tr and vice versa, consequently leading to the production of cytokines with growth promoting functions.
 ...
PMID:Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides. 1629 10

Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.
Breast Cancer Res Treat 2006 Oct
PMID:Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells. 1658 63

Breast cancer has a predilection for metastasis to the bone marrow. The preprotachykinin-I (PPT-I) gene has a central role in the early migration of breast cancer cells into the bone marrow, making this organ a latent repository of the cancer cells. This study investigated whether the invasive and metastatic potential of breast cancer cells correlate with the expression of the PPT-I gene and the receptors for its peptides, neurokinin-1 (NK-1) and NK-2. The studies compared cells that are non-tumorigenic (MCF12A), low metastatic and invasive potential (MCF7), and sublines of MCF with increased invasive and metastatic potential (LCC1 and LCC2). LCC2, but not LCC1 is tamoxifen resistant. Quantitative RT-PCR showed increased expression of PPT-I, NK-1 and NK-2 mRNA LCC1 and LCC2. MCF7 required stimulation by phorbol ester for NK-1 induction. The levels of NK-2 mRNA were significantly increased in LCC2. Clonogenic assays with specific receptor antagonists showed a predominant role for NK-2 in the proliferation of both LCC1 and LCC2. While the growth rate of LCC1 and LCC2 were similar, the latter showed increased migration. Use of a nude mouse model confirmed higher metastatic potential of LCC2, including increased migration to regions of the endosteum. Overall, these studies show a correlation between three neuroendocrine-related genes: PPT-I, NK-1 and NK-2 and the metastatic potential of specific breast cancer cells. These cells provide a model for future studies on bone marrow metastasis.
 ...
PMID:The expression of neurokinin-1 and preprotachykinin-1 in breast cancer cells depends on the relative degree of invasive and metastatic potential. 1664


1 2 3 4 Next >>