GSK3α/ß: A Novel Therapeutic Target for Neuroendocrine Tumors.
Neuroendocrinology
; 106(4): 335-351, 2018.
Article
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| MEDLINE
| ID: mdl-28968593
ABSTRACT
INTRODUCTION:
Glycogen synthase kinase 3α/ß (GSK3α/ß) is a serine/threonine kinase that plays a critical role in cancer.AIMS:
In this study, we evaluated the effects of the specific GSK3α/ß inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/ß signaling in neuroendocrine tumors (NETs). MATERIALS ANDMETHODS:
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/ß inhibition were found and were associated with ß-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/ß 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/ß in NETs and suggest that GSK3α/ß inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tumores Neuroendocrinos
/
Glucógeno Sintasa Quinasa 3 beta
Límite:
Humans
Idioma:
En
Revista:
Neuroendocrinology
Año:
2018
Tipo del documento:
Article