Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin receptors (SSTRs) have been identified in most hormone-producing tumors as well as in breast cancer. In the present study, we determined SSTR1-5 expression in primary ductal NOS breast tumors through semi-quantitative RT-PCR and immunocytochemistry. The results from the analysis of 98 samples were correlated with several key histological markers and receptor expression. All five SSTR subtypes are variably expressed at the mRNA level in breast tumors with 91% of samples showing SSTR1, 98% SSTR2, 96% SSTR3, 76% SSTR4, and 54% SSTR5. SSTR1-5 are localized to both tumor cells and the surrounding peritumoral regions as detected by immunocytochemistry. Levels of SSTR mRNA, when corrected for beta-actin levels, were highest for SSTR3 followed by SSTR1, SSTR2, SSTR5, and SSTR4. Furthermore, there was good correlation between mRNA and protein expression with 84% for SSTR1, 79% for SSTR2, 89% for SSTR3, 68% for SSTR4, 68% for SSTR5, and 78% for all five receptors. SSTR1, 2 and 4 were correlated with ER levels whereas SSTR2 showed an additional correlation with PR levels. These correlations were independent of patient age and histological grade. Moreover, using immunocytochemistry, blood vessels exhibited receptor-specific localization for SSTR2 and SSTR5. Our results indicate significant correlations between mRNA and protein expression along with receptor-specific correlations with histological markers as well as ER and PR levels. Differential distribution of SSTR subtypes in tumors and receptor-specific expression in vascular structures may be considered as a novel diagnosis for breast tumors with receptor subtype agonists.
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PMID:Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1--5 and correlation with receptor protein expression and tumor pathology. 1598 28

The secretion of GH by somatotropes is inhibited by somatostatin (SRIF) through five specific membrane receptors (SSTRs). SRIF increases both transient outward (IA) and delayed rectifying (IK) K+ currents. We aim to clarify the subtype(s) of SSTRs involved in K+ current enhancement in GH3 somatotrope cells using specific SSTR subtype agonists. Expression of all five SSTRs was confirmed in GH3 cells by RT-PCR. Nystatin-perforated patch clamp was used to record voltage-gated K+ currents. We first established the presence of IA and IK type K+ currents in GH3 cells using different holding potentials (-40 or -70 mV) and specific blockers (4-aminopirimidine and tetraethylammonium chloride). SRIF (200 nM) increased the amplitude of both IA and IK in a fully reversible manner. Various concentrations of each specific SRTR agonist were tested on K+ currents to find the maximal effective concentration. Activation of SSTR2 and SSTR4 by their respective agonists, L-779,976 and L-803,087 (10 nM), increased K+ current amplitude without preference to IA or IK, and abolished any further increase by SRIF. Activation of SSTR1 and SSTR5 by their respective agonists, L-797,591 or L-817,818 (10 nM), increased K+ current amplitude, but SRIF evoked a further increase. The SSTR3 agonist L-797,778 (10 nM) did not affect the K+ currents or the response to SRIF. These results indicate that SSTR1, -2, -4, and -5 may all be involved in the enhancement of K+ currents by SRIF but that only the activation of SSTR2 or -4 results in the full activation of K+ current caused by SRIF.
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PMID:Somatostatin increases voltage-gated K+ currents in GH3 cells through activation of multiple somatostatin receptors. 1608 34

The three-dimensional structure of a potent SSTR3-selective analogue of somatostatin, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-Agl(8)(N(beta) Me, 2-naphthoyl)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-Agl(8)(N(beta) Me, 2-naphthoyl)]-SRIF) (peptide 1) has been determined by (1)H NMR in water and molecular dynamics (MD) simulations. The peptide exists in two conformational isomers differing mainly by the cis/trans isomerization of the side chain in residue 8. The structure of 1 is compared with the consensus structural motifs of other somatostatin analogues that bind predominantly to SSTR1, SSTR2/SSTR5 and SSTR4 receptors, and to the 3D structure of a non-selective SRIF analogue, cyclo(3-14)H-Cys(3)-Phe(6)-Tyr(7)-D-2Nal(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)-OH (des-AA(1, 2, 4, 5, 12, 13)[Tyr(7), D-2Nal(8)]-SRIF) (peptide 2). The structural determinant factors that could explain selectivity of peptide 1 for SSTR3 receptors are discussed.
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PMID:Conformational analysis of a potent SSTR3-selective somatostatin analogue by NMR in water solution. 1636 12

We report the comparative efficacy of a somatostatin receptor 1 and 5 subtypes (SSTR2 and SSTR5), and dopamine D2 (DAD2) compound, BIM-23A760, in suppressing GH secretion, in cell culture from human GH-secreting tumors, from patients partially responsive to long-term treatments with octreotide or lanreotide. In 18 tumors tested, the SSTR2, SSTR5, and DAD2 mRNAs were coexpressed. The SSTR2-selective analog, BIM-23197, the SSTR5-selective analog, BIM-23268, and the dopamine (DA) analog, BIM-53097, produced a mean maximal suppression of GH secretion (24 +/- 3, 20 +/- 3, and 20 +/- 3%, respectively) that was similar to that obtained with octreotide (23 +/- 3%). Nevertheless, based on individual responses, 60% of the tumors were mostly sensitive to the SSTR2 analog while 19 and 21% of the tumors were mainly responsive to the SSTR5 analog and to the DA analog, respectively. Among a series of new chimeric compounds that bind the SSTR2, SSTR5, and DAD2 receptors with variable affinities, BIM-23A760 produced greater maximal suppression of GH secretion than octreotide (38 +/- 2 vs 24 +/- 2%; p<0.03). The EC50 for BIM-23A760 was 2 pmol/l. In the presence of sulpride, the dose response inhibition of GH secretion by the trihybrid molecule, BIM-23A760, was partially reversed. The trihybrid produced also a maximal suppression of PRL greater than octreotide (74 +/- 5 vs 46 +/- 11%). When SSTRs pan inhibitors such as BIM-23A779 (binding affinity for SSTR1, SSTR2, SSTR3, SSTR5, respectively: 2.5, 0.3, 0.6, 0.6 nmol/l) or SOM230 were tested for their suppressive effects on GH secretion, they were less potent than the previous dopastatin hybrid molecule. After a brief exposure to a SSTR2-selective analog, BIM-23197, or to a DA analog, BIM-53097, the maximal GH suppression was achieved during 12 h. Under exposure to BIM-23A760, in the same conditions, maximal suppression of GH secretion lasted for 24 h. Such a longer biological effect, yet not explained, probably participates in the higher efficacy of BIM-23A760. The higher efficacy of BIM-23A760 is, at least partially, linked to its high affinity for the SSTR2 receptor subtype (IC50: 3 pmol/l). As compared to the dopastatin compound, the lower efficacy of the universal somatostatin ligands in the inhibition of GH secretion of GH-secreting tumors argues for the use of drugs targeted, according to specific receptors expression and functionality which may vary among the various classes of tumors.
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PMID:BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide. 1662 41

SOM230 is a novel somatostatin analog which shows affinity to 4 of the 5 known somatostatin receptors (SSTR1-5). In binding experiments, SOM230 has a higher affinity to SSTR1, SSTR3 and SSTR5 and a slightly lower affinity to SSTR2 compared to octreotide. In addition, SOM230 has a >7-fold longer plasma half-life than octreotide (11 vs 1.5 h). It was suggested that SOM230 with its broader binding and activity profile compared to octreotide should have a stronger (usually inhibitory) effect on the secretion of hormones. In several animal species, SOM230 was a more potent inhibitor of GH and IGF-I than octreotide. This is in line with a strong expression of both SSTR2 and SSTR5. In the pituitary of patients with primary Cushing's disease, the SSTR5 is more frequently expressed than SSTR2. Accordingly, in rats SOM230 caused a stronger inhibition of ACTH and corticosterone secretion than octreotide. In contrast, most recent experiments showed that octreotide was more potent than SOM230 to inhibit ghrelin secretion in rats. This effect could be explained by the strong expression of SSTR2 in the rat stomach, whereas expression of SSTR3, SSTR4 and SSTR5 was poor or absent. Based on these data it can be concluded that in tissues (or tumors), where several SSTRs are expressed, SOM230 will generally have a stronger effect than octreotide. In cases where SSTR2 is the most important receptor mediating a response (e.g. ghrelin release in rats), the stronger inhibitory effect of octreotide can be explained by its higher affinity for SSTR2. In contrast to the long-lasting inhibitory effect of SOM230 on GH and IGF-I secretion, the inhibitory effects of both compounds on ghrelin show strong tachyphylaxis. These data are in line with the hypothesis that activation of the SSTR2 alone results in a rapid desensitization of the response. If, however, additional SSTR subtypes (especially SSTR5) are expressed and activated by multiligand analogs like SOM230, this might not only form the basis for a stronger response, but also the basis for a reduced tachyphylaxis.
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PMID:Short- and long-term effects of octreotide and SOM230 on GH, IGF-I, ACTH, corticosterone and ghrelin in rats. 1662 42

To determine whether the severity of the catabolic condition differentially regulates the GH axis, male mice were either fed ad libitum or fasted for 12, 24, and 48 h. Hypothalami, pituitaries, and stomachs were collected for assessment of mRNA levels by quantitative real-time RT-PCR, and blood collected for measurement of plasma hormone and metabolite levels by commercial assay kits. Overnight (12 h) fasting resulted in a significant suppression of circulating glucose, insulin, IGF-I, and leptin levels and an increase in corticosterone, free fatty acids, and n-octanoyl ghrelin levels, and these directional changes were maintained at the 24- and 48-h time points. Fasting (24 h) also increased circulating GH levels, which was associated with an increase in pituitary mRNA levels for GHRH receptor and ghrelin receptor and a decrease in mRNA levels for somatostatin (SST) receptor (SSTR) subtypes, SSTR2, SSTR3, and SSTR5, where the changes in ghrelin receptor and SSTR expression persisted after 48 h fasting. Hypothalamic SST mRNA levels were not altered by fasting, whereas there was a transient rise in stomach SST mRNA levels 24 h after food withdrawal. In contrast, there was a biphasic effect of fasting on GHRH expression. GHRH mRNA levels were significantly elevated at 12 and 24 h but fell to approximately 50% of fed controls 48 h after food withdrawal. A sequential rise in hypothalamic neuropeptide Y (NPY) and CRH mRNA levels preceded the fall in GHRH expression, where fasting-induced changes in CRH and GHRH mRNA levels were not observed in 48-h-fasted NPY knockout mice. These observations, in light of previous reports showing both NPY and CRH can inhibit GHRH expression and GH release, suggest that these neuronal systems may work in concert to control the ultimate impact of fasting on GH axis function.
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PMID:Severity of the catabolic condition differentially modulates hypothalamic expression of growth hormone-releasing hormone in the fasted mouse: potential role of neuropeptide Y and corticotropin-releasing hormone. 1703 58

Somatostatin (SST) regulates the function of the central and peripheral nervous system, the endocrine and exocrine organs, as well as the vascular and immune system. These actions are mediated by five specific membrane somatostatin receptors. This study compares the effects on human lymphocytes of two long-acting somatostatin analogues that have different receptor affinity: octreotide and pasireotide. Both analogues have an antiproliferative effect on human lymphocyte proliferation, but they act at different concentration and, while octreotide enhances IL10 and inhibits gamma IFN pasireotide inhibits IL2 and gamma IFN. In both sets of experiment the different behaviour of the two analogues could be due to their different affinity to the SSTR subtypes. Finally this study suggest that the growth inhibitory action of somatostatin analogues is an apoptotic phenomenon and it can be mediated by SSTR2a, in the case of octreotide, and by SSTR3 when pasireotide is used or it can be mediated by the heterodimerization of the two receptor.
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PMID:Inhibitory effect of pasireotide and octreotide on lymphocyte activation. 1711 54

In TSH-secreting pituitary adenomas (TSHoma), octreotide (OCT) therapy reduces tumor size and TSH secretion in some cases but not in others. As OCT acts through various types of somatostatin receptors (SSTRs), the different responses of TSHoma to OCT might be explained by the differences of SSTR expression. We therefore studied the expression of subtype-specific SSTR mRNA transcripts in tumor tissues by RT-PCR. Type 2 (SSTR2) mRNA transcripts were detected in all 8 tumors but those of SSTR3 and SSTR5 were demonstrated only in 5 of them. Serum TSH levels were decreased by OCT administration test in all patients but OCT therapy was effective in two patients out of three. SSTR5 mRNA was detected in two tumors from the responder, but not in one tumor that was resistant to OCT. These observations suggest that the temporal decrease of TSH by OCT may be mediated by SSTR2, and that the long term response to OCT therapy may be related with the expression of SSTR5. Therefore, the expression of SSTR5 in TSHoma may be a useful marker for predicting the outcome of the therapy, but further studies with larger numbers of patients are necessary.
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PMID:Expression of type 5 somatostatin receptor in TSH-secreting pituitary adenomas: a possible marker for predicting long-term response to octreotide therapy. 1715 1

Small intestinal carcinoids (SICs) are the most prevalent gastrointestinal carcinoid and characterized by local invasion metastasis and protean symptomatology. The proliferative and secretory regulation of the cell of origin, the enterochromaffin (EC) cell has not been characterized. The absence of either a pure preparation of normal EC cells or human EC carcinoid cell lines has hindered the development of therapeutic agents. We therefore further characterized the neoplastic SIC cell line, KRJ-I by assessing its secretory (serotonin (5-HT)) and proliferative responses and defining its log growth phase transcriptome. Electron microscopy demonstrated oval, lobulated nuclei and substance P, and 5-HT-positive cytoplasmic vesicles. RT-PCR detected transcripts for chromogranin A (CHGA), VMAT1 (SLC18A1), tryptophan hydroxylase (TPH1), substance P (TAC1), guanylin (GUCA2A), and SERT (SLC6A4). By immunohistochemistry, all cells were positive for CHGA, SERT, VMAT1, and TPH1. Transcriptome analysis (Affymetrix U133 Plus chips) identified somatostatin SSTR2/3, adrenergic alpha1C and beta1, dopamine D2, nicotinic-type cholinergic A5, A6, B1, muscarinic acetylcholine M4, and 5-HT-2A receptors. The presence of transcripts for SSTR1, SSTR2, and SSTR3 receptors was confirmed by RT-PCR and sequencing. Isoproterenol (ISO) resulted in a dose-dependent increase in intracellular cAMP (EC50=340 nM) and 5-HT (EC50=81 nM) which was completely inhibited by the cAMP antagonist 2',5'-dideoxyadenosine (10 microM). Preincubation with a SSTR agonist, lanreotide, inhibited Ip-stimulated 5-HT secretion (IC50=420 nM). Both lanreotide (10 nM) and rapamycin (50 nM) inhibited proliferation (20+/-12 and 35+/-5% respectively) in serum-free medium whereas gefitinib (1 nM-10 microM) inhibited proliferation at micromolar concentrations. KRJ-I is a neoplastic EC cell line that can be used as an in vitro model of SICs as it will allow elucidation and clarification of the secretory and proliferative mechanism(s) of neoplastic EC cells and the molecular signatures that characterize each of these responses.
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PMID:Further delineation of the continuous human neoplastic enterochromaffin cell line, KRJ-I, and the inhibitory effects of lanreotide and rapamycin. 1724 79

The secretion of growth hormone (GH) is inhibited by hypothalamic somatostatin (SRIF) in somatotropes through five subtypes of the somatostatin receptor (SSTR1-SSTR5). We aimed to characterize the subtype(s) of SSTRs involved in the Ca2+ current reduction in GH3 somatotrope cells using specific SSTR subtype agonists. We used nystatin-perforated patch clamp to record voltage-gated Ca2+ currents, using a holding potential of -80 mV in the presence of K+ and Na+ channel blockers. We first established the presence of T-, L-, N-, and P/Q-type Ca2+ currents in GH3 cells using a variety of channel blockers (Ni+, nifedipine, omega-conotoxin GVIA, and omega-agatoxin IVA). SRIF (200 nM) reduced L- and N-type but not T- or P/Q-type currents in GH3 cells. A range of concentrations of each specific SSTR agonist was tested on Ca2+ currents to find the maximal effective concentration. Activation of SSTR2 with 10(-7) and 10(-8) M L-797,976 decreased the voltage-gated Ca2+ current and abolished any further decrease by SRIF. SSTR1, SSTR3, SSTR4, and SSTR5 agonists at 10(-7) M did not modify the voltage-gated Ca2+ current and did not affect the Ca2+ current response to SRIF. These results indicate that SSTR2 is involved mainly in regulating voltage-gated Ca2+ currents by SRIF, which contributes to the decrease in intracellular Ca2+ concentration and GH secretion by SRIF.
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PMID:Somatostatin decreases voltage-gated Ca2+ currents in GH3 cells through activation of somatostatin receptor 2. 1732 72


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