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Original Paper

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

Aristizabal Prada E.T.a · Weis C.a · Orth M.b-e · Lauseker M.f · Spöttl G.a · Maurer J.a · Grabowski P.g,h · Grossman A.i,j · Auernhammer C.J.a · Nölting S.a

Author affiliations

aDepartment of Internal Medicine IV, Campus Grosshadern, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System (GEPNET-KUM), University Hospital, Ludwig-Maximilians University of Munich, and bDepartment of Radiation Oncology, Campus Grosshadern, University Hospital, Ludwig-Maximilians University of Munich, Munich, cClinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum München, Neuherberg, dGerman Cancer Consortium (DKTK), Munich, eGerman Cancer Research Center (DKFZ), Heidelberg, fInstitute for Medical Information Sciences, Biometry, and Epidemiology, Campus Grosshadern, Ludwig-Maximilians University of Munich, Munich, gDepartment of Gastroenterology, CC13 (CBF and CVK), Charité - Universitätsmedizin Berlin, Berlin, and hDepartment of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany; iOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, and jRoyal Free Hospital ENETS Centre of Excellence, London, UK

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 30, 2017
Accepted: September 27, 2017
Published online: October 02, 2017

Number of Print Pages: 17
Number of Figures: 7
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

Abstract

Introduction: Glycogen synthase kinase 3α/β (GSK3α/β) is a serine/threonine kinase that plays a critical role in cancer. Aims: In this study, we evaluated the effects of the specific GSK3α/β inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/β signaling in neuroendocrine tumors (NETs). Materials and Methods: Human NET cell lines (BON1, QGP1, H727, and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU), and γ-irradiation. Results: AR-A014418 significantly dose- and time-dependently decreased cell viability in all 4 NET cell lines through inhibition of epithelial growth factor receptor and mTORC1/p70S6K signaling, as well as cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. Apoptosis induction was observed in H727, GOT1 and QGP1 cells, but not in BON1 cells. Furthermore, significant antimigratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/β inhibition was prevented by combining AR-A014418 with the ERK and Akt inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemosensitizing effects on 5-FU in QGP1 and slight radiosensitizing properties in BON1 and QGP1 cells. Conclusion: Our data provide new insights into the role of GSK3α/β in NETs and suggest that GSK3α/β inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity.

© 2017 S. Karger AG, Basel


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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 30, 2017
Accepted: September 27, 2017
Published online: October 02, 2017

Number of Print Pages: 17
Number of Figures: 7
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN


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