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.
Held-Feindt
J
J
Department of Anatomy, University of Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany. held-feiundt@anat.uni-kiel.de
Forstreuter
F
F
Pufe
T
T
Mentlein
R
R
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