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GSK3α/β: A novel therapeutic target for neuroendocrine tumors.
Neuroendocrinology 106, 335-351 (2018)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Combination Treatment ; Gsk3α/β Inhibition ; Neuroendocrine Tumors; Planarian Schmidtea-mediterranea; Stem-cells; Rna-seq; Gene-expression; Regeneration; Pluripotency; Trajectories; Organism; Tissues; System
ISSN (print) / ISBN
0028-3835
e-ISSN
1423-0194
Journal
Neuroendocrinology
Quellenangaben
Volume: 106,
Issue: 4,
Pages: 335-351
Publisher
Karger
Publishing Place
1200 New York Ave, Nw, Washington, Dc 20005 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)