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Prada, A.E.T.* ; Weis, C.* ; Orth, M. ; Lauseker, M.* ; Spoettl, G.* ; Maurer, J.* ; Grabowski, P.* ; Grossman, A.B.* ; Auernhammer, C.J.* ; Noelting, S.*

GSK3α/β: A novel therapeutic target for neuroendocrine tumors.

Neuroendocrinology 106, 335-351 (2018)
Verlagsversion Postprint DOI
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Combination Treatment ; Gsk3α/β Inhibition ; Neuroendocrine Tumors; Planarian Schmidtea-mediterranea; Stem-cells; Rna-seq; Gene-expression; Regeneration; Pluripotency; Trajectories; Organism; Tissues; System
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 0028-3835
e-ISSN 1423-0194
Zeitschrift Neuroendocrinology
Quellenangaben Band: 106, Heft: 4, Seiten: 335-351 Artikelnummer: , Supplement: ,
Verlag Karger
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Translational Metabolic Oncology (IDC-TMO)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Radiation Sciences
PSP-Element(e) G-521800-001
DOI 10.1159/000481887
WOS ID WOS:000433960100005
Scopus ID 85048052366
Erfassungsdatum 2018-07-09
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