Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells.
The somatostatin receptor subtype sst2A is highly expressed, non-mutated and functionally active in gliomas. After stimulation of cultivated human U343 glioma cells with somatostatin, octreotide (sst2-, sst3- and sst5-selective peptide agonist) or the sst2-selective non-peptide agonist L-054,522 multiple signal transduction pathways are induced: elevated cAMP levels are reduced, protein tyrosine phosphatases (especially SHP2) are activated and mitogen-activated protein kinases are inhibited. Stimulation of the phosphatases resulted in dephosphorylation of activated receptors for EGF and PDGF (epidermal and platelet-derived growth factor), and as a consequence the mitogen-activated protein kinases ERK 1 and 2 (p42/p44) were de-phosphorylated in co-stimulation experiments. Furthermore, somatostatin or sst2-selective agonists reduced EGF-stimulated expression of the AP-1 complex (c-jun/c-jun) on the transcriptional and translational level. These experiments show that the interaction of stimulatory and inhibitory receptors are important mechanisms for the regulation of signal cascades and gene expression.
Department of Anatomy, University of Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany. held-feiundt@anat.uni-kiel.de
J
J
Held-Feindt
F
F
Forstreuter
T
T
Pufe
R
R
Mentlein
D001562:Benzimidazoles / Q000494:pharmacology; D001932:Brain Neoplasms; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001562:Benzimidazoles; D006728:Hormones; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C114420:L 054522; D016755:Proto-Oncogene Proteins c-jun; D017481:Receptors, Somatostatin; D018808:Transcription Factor AP-1; D013004:Somatostatin; C093733:somatostatin receptor 2; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D015282:Octreotide