Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients

Waser, Beatrice; Cescato, Renzo; Liu, Qisheng; Kao, Yachu J; Körner, Meike; Christ, Emanuel; Schonbrunn, Agnes; Reubi, Jean Claude (2012). Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. American journal of pathology, 180(5), pp. 1942-9. New York, N.Y.: Elsevier 10.1016/j.ajpath.2012.01.041

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Endocrinology, Diabetology and Clinical Nutrition

UniBE Contributor:

Cescato, Renzo; Körner Jachertz, Meike; Christ, Emanuel and Reubi, Jean-Claude

ISSN:

0002-9440

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:26

Last Modified:

06 Dec 2013 13:31

Publisher DOI:

10.1016/j.ajpath.2012.01.041

PubMed ID:

22538189

Web of Science ID:

000303641000019

URI:

https://boris.unibe.ch/id/eprint/9377 (FactScience: 215107)

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