Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells

Held‐Feindt, Janka; Forstreuter, Frauke; Pufe, Thomas; Mentlein, Rolf

doi:10.1016/s0169-328x(00)00225-4

Cited by 43 publications

(29 citation statements)

References 26 publications

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“…We have not observed side effects induced by SOM230 treatment, and although possible insulin inhibition and the inherent risk of diabetes have been described [50,51], these did not occur, with the exception of 3 dogs, in which glycemia became normal after treatment with low doses of insulin detemir. Nevertheless, it is not ascertained that the hyperglycemia in these animals was caused by SOM230 treatment, because in our observations, 12–15% of dogs that suffer of Cushing’s disease develop diabetes independently of the treatment they receive, while 1–2 out of 10 dogs that come to the veterinary clinic to consult for Cushing’s disease already have diabetes once the diagnosis of Cushing’s is confirmed [Castillo, unpubl.…”

Section: Discussionmentioning

confidence: 66%

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

et al. 2011

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SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing’s disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing’s disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G_i α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing’s disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing’s disease.

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Section: Discussionmentioning

confidence: 66%

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

et al. 2011

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“…Downstream inhibitory effects of SS on the growth factor-induced signaling cascade included the reduction of phosphorylation of ERK-1/-2, of the transcription factor c-jun and of the activity of the AP-1-complex. 26 This suggest that SS interferes with the MAP kinase pathway or activation of the AP-1 complex to reduce VEGF production.…”

Section: Discusssionmentioning

confidence: 99%

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

et al. 2001

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In various cell types, the neuro-and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factorinduced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.

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“…Alternatively, PTP may act at several different levels to dephosphorylate GHR, JAK2, and STAT5b. SRIF has been shown to dephosphorylate the epidermal growth factor and platelet-derived growth factor receptors (45,46), members of the cytokine receptor superfamily that includes the GHR, which signal via JAK2 and the STAT proteins. The observation that GH-induced phosphorylation of ERK remained unaffected, while STAT5b was dephosphorylated by coincubation of GH with SRIF, lends support to the selective dephosphorylation of STAT5b, as previously described for SHP-I (34).…”

Section: Figurementioning

confidence: 99%

Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis

Murray¹,

Kim²,

Ren³

et al. 2004

J. Clin. Invest.

139

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Somatostatin (SRIF) analogs provide safe and effective therapy for acromegaly. In a proportion of patients, however, SRIF analogs may lead to discordant growth hormone (GH) and IGF-I suppression, which suggests a more complex mechanism than attributable to inhibition of GH release alone. To elucidate whether SRIF acts peripherally on the GH-IGF-I axis, we showed that rat hepatocytes express somatostatin receptor subtypes-2 and -3 and that IGF-I mRNA and protein levels were suppressed in a dose-dependent manner by administration of octreotide. The inhibitory effect of SRIF was not apparent without added GH and in the presence of GH was specific for IGF-I induction and did not inhibit GH-induced c-myc or extracellular signal regulated kinase (ERK) phosphorylation. Pertussis toxin treatment of hepatocytes incubated with GH and SRIF, or with GH and octreotide, abrogated the inhibitory effect on GH-induced IGF-I, which confirms the requirement for the inhibitory G-protein. Treatment with SRIF and GH increased protein tyrosine phosphatase (PTP) activity and inhibited signal transducer and activator of transcription-5b (STAT5b) phosphorylation and nuclear localization. Octreotide also inhibited GH-stimulated IGF-I protein content of ex vivo-perfused rat livers. The results demonstrate that SRIF acts both centrally and peripherally to control the GH-IGF-I axis, providing a mechanistic explanation for SRIF analog action in treating patients with GH-secreting pituitary adenomas.

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Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells

Cited by 43 publications

References 26 publications

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis

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