%0 Generic %A E.T., Aristizabal Prada %A C., Weis %A M., Orth %A M., Lauseker %A G., Spöttl %A J., Maurer %A P., Grabowski %A A., Grossman %A C.J., Auernhammer %A S., Nölting %D 2017 %T Supplementary Material for: GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors? %U https://karger.figshare.com/articles/dataset/Supplementary_Material_for_GSK3_A_Novel_Therapeutic_Target_for_Neuroendocrine_Tumors_/5607232 %R 10.6084/m9.figshare.5607232.v1 %2 https://ndownloader.figshare.com/files/9757030 %2 https://ndownloader.figshare.com/files/9757033 %2 https://ndownloader.figshare.com/files/9757036 %2 https://ndownloader.figshare.com/files/9757039 %2 https://ndownloader.figshare.com/files/9757042 %2 https://ndownloader.figshare.com/files/9757045 %2 https://ndownloader.figshare.com/files/9757048 %2 https://ndownloader.figshare.com/files/9757051 %K GSK3α/β inhibition %K Neuroendocrine tumors %K Combination treatment %X

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.

%I Karger Publishers