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Original Paper

Advanced Release (accepted, unedited manuscript)

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

Aristizabal Prada E · Weis C. · Orth M. · Lauseker M. · Spöttl G · Maurer J · Grabowski P · Grossman A · Auernhammer C · Nölting S

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Article / Publication Details

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

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

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

Abstract


Introduction: GSK3α/β is a serine/threonine-kinase that plays a critical role in cancer. Aim(s): 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 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 four NET cell lines through inhibition of EGFR- 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. However, apoptosis induction was only observed in H727 cells. Furthermore, significant anti-migratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory up-regulation 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 chemo-sensitizing effects to 5-FU in QGP1 and slight radio-sensitizing 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.

©2017S. Karger AG, Basel


Article / Publication Details

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

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

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


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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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