In:
Neuroendocrinology, S. Karger AG, Vol. 106, No. 4 ( 2018), p. 335-351
Abstract:
〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 Glycogen synthase kinase 3α/β (GSK3α/β) is a serine/threonine kinase that plays a critical role in cancer. 〈 b 〉 〈 i 〉 Aims: 〈 /i 〉 〈 /b 〉 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). 〈 b 〉 〈 i 〉 Materials and Methods: 〈 /i 〉 〈 /b 〉 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 & #x03B3;-irradiation. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 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.
Type of Medium:
Online Resource
ISSN:
0028-3835
,
1423-0194
Language:
English
Publisher:
S. Karger AG
Publication Date:
2018
detail.hit.zdb_id:
1483028-0
