GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors?

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.



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