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Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors

CONTEXT: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models. SETTING AND DESIGN: The cell lines HC45 and...

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Autores principales: Fotouhi, Omid, Kjellin, Hanna, Larsson, Catharina, Hashemi, Jamileh, Barriuso, Jorge, Juhlin, C. Christofer, Lu, Ming, Höög, Anders, Pastrián, Laura G., Lamarca, Angela, Soto, Victoria Heredia, Zedenius, Jan, Mendiola, Marta, Lehtiö, Janne, Kjellman, Magnus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052342/
https://www.ncbi.nlm.nih.gov/pubmed/27459532
http://dx.doi.org/10.1210/jc.2016-2028
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author Fotouhi, Omid
Kjellin, Hanna
Larsson, Catharina
Hashemi, Jamileh
Barriuso, Jorge
Juhlin, C. Christofer
Lu, Ming
Höög, Anders
Pastrián, Laura G.
Lamarca, Angela
Soto, Victoria Heredia
Zedenius, Jan
Mendiola, Marta
Lehtiö, Janne
Kjellman, Magnus
author_facet Fotouhi, Omid
Kjellin, Hanna
Larsson, Catharina
Hashemi, Jamileh
Barriuso, Jorge
Juhlin, C. Christofer
Lu, Ming
Höög, Anders
Pastrián, Laura G.
Lamarca, Angela
Soto, Victoria Heredia
Zedenius, Jan
Mendiola, Marta
Lehtiö, Janne
Kjellman, Magnus
author_sort Fotouhi, Omid
collection PubMed
description CONTEXT: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models. SETTING AND DESIGN: The cell lines HC45 and H727 were treated with 10nM lanreotide for different time periods and alterations of the proteome were analyzed by in-depth high-resolution isoelectric focusing tandem liquid chromatography-mass spectrometry. We next investigated whether the observed suppression of survivin was mediated by adenomatous polyposis coli (APC) and possible effects on tumor proliferation in vitro. Expression of survivin was assessed by immunohistochemistry in 112 NET cases and compared with patient outcome. RESULTS: We quantified 6451 and 7801 proteins in HC45 and H727, respectively. After short time lanreotide treatment APC was increased and survivin reduced. Overexpression of APC in H727 cells decreased, and APC knock-down elevated the survivin level. The lanreotide regulation of APC-survivin could be suppressed by small interfering RNA against somatostatin receptor 2. Although lanreotide only gave slight inhibition of proliferation, targeting of survivin with the small molecule YM155 dramatically reduced proliferation. Moderate or high as compared with low or absent total survivin expression was associated with shorter progression-free survival, independent of tumor stage, grade, and localization. CONCLUSIONS: We report a proteome-wide analysis of changes in response to lanreotide in NET cell lines. This analysis suggests a connection between somatostatin analog, APC, and survivin levels. Survivin is a possible prognostic factor and a new potential therapeutic target in NETs.
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spelling pubmed-50523422016-10-18 Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors Fotouhi, Omid Kjellin, Hanna Larsson, Catharina Hashemi, Jamileh Barriuso, Jorge Juhlin, C. Christofer Lu, Ming Höög, Anders Pastrián, Laura G. Lamarca, Angela Soto, Victoria Heredia Zedenius, Jan Mendiola, Marta Lehtiö, Janne Kjellman, Magnus J Clin Endocrinol Metab Original Articles CONTEXT: Somatostatin analogs are established in the treatment of neuroendocrine tumors (NETs) including small intestinal NET; however, the molecular mechanisms are not well known. Here, we examined the direct effects of lanreotide in NET cell line models. SETTING AND DESIGN: The cell lines HC45 and H727 were treated with 10nM lanreotide for different time periods and alterations of the proteome were analyzed by in-depth high-resolution isoelectric focusing tandem liquid chromatography-mass spectrometry. We next investigated whether the observed suppression of survivin was mediated by adenomatous polyposis coli (APC) and possible effects on tumor proliferation in vitro. Expression of survivin was assessed by immunohistochemistry in 112 NET cases and compared with patient outcome. RESULTS: We quantified 6451 and 7801 proteins in HC45 and H727, respectively. After short time lanreotide treatment APC was increased and survivin reduced. Overexpression of APC in H727 cells decreased, and APC knock-down elevated the survivin level. The lanreotide regulation of APC-survivin could be suppressed by small interfering RNA against somatostatin receptor 2. Although lanreotide only gave slight inhibition of proliferation, targeting of survivin with the small molecule YM155 dramatically reduced proliferation. Moderate or high as compared with low or absent total survivin expression was associated with shorter progression-free survival, independent of tumor stage, grade, and localization. CONCLUSIONS: We report a proteome-wide analysis of changes in response to lanreotide in NET cell lines. This analysis suggests a connection between somatostatin analog, APC, and survivin levels. Survivin is a possible prognostic factor and a new potential therapeutic target in NETs. Endocrine Society 2016-10 2016-07-26 /pmc/articles/PMC5052342/ /pubmed/27459532 http://dx.doi.org/10.1210/jc.2016-2028 Text en http://creativecommons.org/licenses/by-nc/4.0/ This article is published under the terms of the Creative Commons Attribution-Non Commerical License (CC-BY-NC; http://creativecommons.org/licenses/by-nc/4.0/).
spellingShingle Original Articles
Fotouhi, Omid
Kjellin, Hanna
Larsson, Catharina
Hashemi, Jamileh
Barriuso, Jorge
Juhlin, C. Christofer
Lu, Ming
Höög, Anders
Pastrián, Laura G.
Lamarca, Angela
Soto, Victoria Heredia
Zedenius, Jan
Mendiola, Marta
Lehtiö, Janne
Kjellman, Magnus
Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title_full Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title_fullStr Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title_full_unstemmed Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title_short Proteomics Suggests a Role for APC-Survivin in Response to Somatostatin Analog Treatment of Neuroendocrine Tumors
title_sort proteomics suggests a role for apc-survivin in response to somatostatin analog treatment of neuroendocrine tumors
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052342/
https://www.ncbi.nlm.nih.gov/pubmed/27459532
http://dx.doi.org/10.1210/jc.2016-2028
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