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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) represent a rare and highly heterogeneous entity that often is revealed by vague and non-specific symptoms, leading to a delayed diagnosis. Here we will review some of the most regularly observed false positive and false negative cases and provide clues to recognize and manage them properly. Particularly, the value of chromogranin-A as a serum tumour marker and Somatostatin receptor scintigraphy as an imaging test, are reviewed. Indeed, chromogranin-A and other hormones, such as gastrin, as well as urinary 5-hydroxy-indolic acetic acid (5-HIAA) are often tested to diagnose NET without appraising the clinical situation, leading to extensive work-up on false bases. On the other hand, some tests are performed in situations where they do not add additional information (e.g. 5-HIAA in pancreatic or rectal NET) because invariably negative. Somatostatin receptor scintigraphy is an expensive examination, still not reimbursed in Belgium, for which indications must be carefully assessed, knowing its specificity and sensitivity.
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PMID:Diagnostic pitfalls in digestive neuroendocrine tumours. 1940 68

Somatostatin analogs (SSAs) have an important role in the management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP NETs). These compounds can control the symptoms induced by the production of hormones and peptides. The antiproliferative effects of SSAs and especially tumour shrinkage are less obvious in patients with GEP NETs than in those with acromegaly. However, based upon phase II experience there is a strong suggestion of a disease stabilizing effect of SSAs in selected patients. Those patients with a progressive, non-functional GEP NET, positive octreotide scintigraphy, a low proliferation index and in the absence of surgical options may benefit from a first-line medical therapy with SSAs. The exploration of the mechanisms of this effect are unclear and hampered by the lack of suitable preclinical models. The better understanding of the tumour biology of GEP NETs, together with the development of new SSAs with better affinity on all somatostatin receptors, represent an unmet medical need.
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PMID:The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. 1940 73

The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressed and stimulated by its ligand somatostatin in pancreatic cancer. We reveal a mechanism underlying oncosuppressive action of sst2, whereby this inhibitory receptor upregulates the expression of the secreted angioinhibitory factor thrombospondin-1 (TSP-1), as demonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation of TSP-1 occurs through the inhibition of the PI3K pathway. It depends on transcriptional and translational events, involving a previously undescribed IRES in the 5'-UTR of TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivo model to demonstrate that TSP-1 is a critical effector of the inhibitory role of sst2 on the neoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced in vitro tubulogenesis of endothelial cells when grown in conditioned medium from pancreatic cancer cells expressing sst2, as compared to those expressing the control vector. TSP-1 inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenic factor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation in endothelial cells. Using human pancreatic tissue-microarrays, the expression of both sst2 and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Both proteins are nearly undetectable in normal exocrine pancreas and in most invasive cancer lesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacent lesions. The upregulation of both sst2 and TSP-1 tumor suppressors may function as an early negative feedback to restrain pancreatic carcinogenesis.
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PMID:Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer. 1980

Ca(2+) influx through L-type voltage-gated Ca(2+) channels (L-VSCC) is required for K(+)-induced somatostatin (SS) mRNA. Increase in intracellular Ca(2+) concentration leads to the activation of cyclic AMP-responsive element binding protein (CREB), a key regulator of SS gene transcription. Several different protein kinases possess the capability of driving CREB upon membrane depolarization. We investigated which of the signalling pathways involved in CREB activation mediates SS gene induction in response to membrane depolarization in cerebrocortical cells exposed to 56 mM K(+). Activity dependent phosphorylation of CREB in Ser(133) was immunodetected. Activation of CREB was biphasic showing two peaks at 5 and 60 min. The selective inhibitors of extracellular signal related protein kinase/mitogen-activated protein kinase (ERK/MAPK) PD098059, cyclic-AMPdependent protein kinase (cAMP/PKA) H89 and RpcAMPS, and Ca(2+)/calmodulin-dependent protein kinases (CaMKs) pathways KN62 and KN93 were used to determine the signalling pathways involved in CREB activation. Here we show that the early activation of CREB was dependent on cAMP/PKA along with CaMKs pathways whereas the ERK/MAPK and CaMKs were implicated in the second peak. We observed that H89, RpcAMPS, KN62 and KN93 blocked K(+)-induced SS mRNA whereas PD098059 did not. These findings indicate that K(+)-induced SSmRNA is mediated by the activation of cAMP/PKA and CaMKs pathways, thus suggesting that the early activation of CREB is involved in the induction of SS by neuronal activity. We also demonstrated, using transient transfections of cerebrocortical cells, that K(+) induces the transcriptional regulation of the SS gene through the cAMP-responsive element (CRE) sequence located in the SS promoter.
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PMID:Activity-dependent somatostatin gene expression is regulated by cAMP-dependent protein kinase and Ca2+-calmodulin kinase pathways. 1985 66

Molecular targeted cancer therapy (MTCT) is the "personalized" or "individualized" approaches toward cancer which targets the particular molecular or genetic changes, i.e. over-expression of molecules, and genetic amplification, mutations and translocations. MTCT is generally composed of two mechanisms, (1) humanized monoclonal antibodies (hMAB) and (2) tyrosine kinase inhibitors (TKI). Somatostatin analogue (SA) is the unique situation for the therapy of neuroendocrine tumors (NETs) which possess somatostatin receptor (SSTR). The cancers which are benefited by MTCT have been increased and will be increased to cover wide varieties of cancers. Good examples are (1) trastuzumab, hMAB against HER2 in breast cancers with HER2 over-expression and amplification, (2) imatinib, TKI, for gastrointestinal stromal tumors (GISTs) with c-kit mutation, (3) gefitinib, TKI, for lung adenocarcinoma with EGFR mutation. The drug effects have been reported to be associated with these molecular and genetic changes. It should be particularly emphasized to treat the patients with corresponding targeted molecular changes. These molecular and genetic analysis should be performed! On the right areas of the cancers, ample amount of viable cancer cells, where the major roles of pathologists are lied. This introductory review of MTCT describes more details of each MTCT.
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PMID:Roles of pathologists in molecular targeted cancer therapy. 1989 8

Somatostatin analogs that activate the somatostatin subtype 2A (sst2A) receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable of activating multiple somatostatin receptor subtypes have been developed to increase tumor responsiveness. We tested two such multi-somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells, somatostatin inhibited cAMP production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells; pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin's actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.
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PMID:Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways. 1991 Apr 53

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.
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PMID:A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases. 2003 67

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH(2)-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.
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PMID:Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: involvement of up-regulation of BMP receptor signaling by somatostatin analogs. 2005 21

Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are rare tumours that present many clinical features.They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects.In 2000 the WHO developed a new classification which gives a better description of the characteristics and biological behaviour of the tumour.Surgical resection is the treatment of first choice for a patient with a GEP NET. In metastatic disease multiple therapeutic approaches are possible. In these cases the goal is to improve quality of life and to extent survival.GEP NETs express somatostatin receptors (SSTRs), which are bound by somatostatin (SST) or its synthetic analogues, although the subtypes and number of SSTRs expressed is very variable.Somatostatin analogues are used frequently to control hormone-related symptoms while their anti-neoplastic activity, even if it has not been widely studied and the regarding data are discordant, seems to result prevalently in tumour stabilisation.A few patients who fail to respond or cease to respond to standard SST analogues treatment seem to have a response to higher doses of these drugs.The use of higher doses of somatostatin analogues or the development of new subtype selective agonists and chimaeric somatostatin analogues, or pan-somatostatin will probably improve the clinical management of these patients.This review provides an update on the use of somatostatin analogues in the management of GEP NETs and discusses novel clinical strategies based on SSTR 2 gene transfer therapy.
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PMID:Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. 2019 64

Gastric neuroendocrine tumors (NET ventriculi) are rare neoplasms of the gastrointestinal tract, increasing in incidence over last fifty years, what partly could be explained by the common use of upper gastrointestinal tract endoscopy. Pathogenesis of the NET ventriculi is not fully understood, however it is well known, that in all NET ventriculi types there is a hyperplasia of enterochromaffine-like cells (ECL) related to different stimuli. NET ventriculi type 1 is related to autoimmunological atrophic gastritis and hypergastrinaemia, NET ventriculi type 2 with hypergastrinemia in the course of Zollinger-Ellison syndrome associated with multiple endocrine neoplasia (MEN 1) syndrome, NET ventriculi type 3 are sporadic tumors not related to hypergastrinaemia, usually with poor prognosis. Localization of tumors and possible metastases, histo-pathological confirmation of the neoplasm type and defining the source of hypergastrinaemia is essential in diagnostic of NET ventriculi. Treatment dependent on the NET ventriculi type is based on endoscopic or surgical tumor excision in type 1 and 2 and surgical radical treatment in type 3. There is an increased interest in the use of somatostatin analogues (SSA) both in type 1 and in cases with dissemination of the disease. Advances in understanding of the pathogenesis and recent development of medical techniques leads to the improvement of diagnostic and therapy in these group of neoplasms.
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PMID:[Current opinions on pathogenesis, diagnostic procedures and management of gastric neuroendocrine tumors]. 2051 5


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