Document Detail


Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients.
MedLine Citation:
PMID:  22538189     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Somatostatin analogues, which are used to treat neuroendocrine tumors, target the high levels of somatostatin receptor subtype 2 (SSTR1; alias sst2) expressed in these cancers. However, some tumors are resistant to somatostatin analogues, and it is unknown whether the defect lies in sst2 activation or downstream signaling events. Because sst2 phosphorylation occurs rapidly after receptor activation, we examined whether sst2 is phosphorylated in neuroendocrine tumors. The sst2 receptor phosphorylation was evaluated by IHC and Western blot analysis with the new Ra-1124 antibody specific for the sst2 receptor phosphorylated at Ser341/343 in receptor-positive neuroendocrine tumors obtained from 10 octreotide-treated and 7 octreotide-naïve patients. The specificity, time course, and subcellular localization of sst2 receptor phosphorylation were examined in human embryo kinase-sst2 cell cultures by immunofluorescence and confocal microscopy. All seven octreotide-naïve tumors displayed exclusively nonphosphorylated cell surface sst2 expression. In contrast, 9 of the 10 octreotide-treated tumors contained phosphorylated sst2 that was predominantly internalized. Western blot analysis confirmed the IHC data. Octreotide treatment of human embryo kinase-sst2 cells in culture demonstrated that phosphorylated sst2 was localized at the plasma membrane after 10 seconds of stimulation and was subsequently internalized into endocytic vesicles. These data show, for the first time to our knowledge, that phosphorylated sst2 is present in most gastrointestinal neuroendocrine tumors from patients treated with octreotide but that a striking variability exists in the subcellular distribution of phosphorylated receptors among such tumors.
Authors:
Beatrice Waser; Renzo Cescato; Qisheng Liu; Yachu J Kao; Meike Körner; Emanuel Christ; Agnes Schonbrunn; Jean Claude Reubi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The American journal of pathology     Volume:  180     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-27     Completed Date:  2012-08-06     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1942-9     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Affiliation:
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Hormonal / pharmacology*,  therapeutic use
Carcinoma, Neuroendocrine / drug therapy,  metabolism*,  surgery
Chemotherapy, Adjuvant
Humans
Microscopy, Confocal
Microscopy, Fluorescence
Neoplasm Proteins / drug effects,  metabolism
Octreotide / pharmacology*,  therapeutic use
Phosphorylation / drug effects
Receptors, Somatostatin / drug effects,  metabolism*
Grant Support
ID/Acronym/Agency:
DK032234/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Hormonal; 0/Neoplasm Proteins; 0/Receptors, Somatostatin; 0/somatostatin receptor 2; 83150-76-9/Octreotide
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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