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.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin > Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 1423-0194 |
| Sprache: | Englisch |
| Dokumenten ID: | 41532 |
| Datum der Veröffentlichung auf Open Access LMU: | 15. Dez. 2017, 08:04 |
| Letzte Änderungen: | 04. Nov. 2020, 13:17 |
- Dokument bearbeiten
