Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

“…significant effects on other signaling pathways, were obtained at concentrations at which both isoforms were inhibited: this might be explained by the fact that both molecules have distinct roles and functionalities [10]. Only in QGP1 cells GSK3α inhibition alone was able to trigger a full cellular response, similar to a study with neuroblastoma cells where AR-A014418 showed growth inhibition after sole GSKα phosphorylation at concentrations up to 20 µM [35].…”

“…Similar results regarding apoptosis induction and a decrease in Bcl2 after GSK3α/β inhibition were described recently for different cancer cell entities in vitro [12,16,24] including NETs [21]. Furthermore, neuroblastoma cell growth inhibition after treatment with AR-A014418 was due to apoptosis induction [35]. However, in BON1 cells even a decrease in cleaved caspase 3/7 at 72 h and 144 h of treatment and an increase in antiapoptotic Bcl2 were observed.…”

“…Due to a previously reported negative regulation of cell cycle proteins by active GSK3β [19], we would have expected an increase in cyclin D1 and D3 in response to GSK3β inhibition, which could not be confirmed in the less sensitive cell lines BON1, QGP1, and H727. In neuroblastoma cells, a decrease in the related cyclin D1 was also observed after AR-A014418 treatment [35]. In contrast, in the most sensitive GOT1 cells, there was no expression of cyclin D1 and an increase in cyclin D3 at 20 μM AR-A014418.…”

“…Similarly, accumulation of β-catenin has been associated with an enhanced migratory potential, affecting migrationpromoting factors [72,73]. Furthermore, reduction of β-catenin expression after AR-A014418 treatment was also observed in neuroblastoma cells [35]. This might be explained by the fact that GSK3β has been shown to be implicated not only in the degradation of β-catenin, but also in the stabilization of β-catenin through specific complex phosphorylation [10].…”

“…We chose the AR-A014418 (effective doses ≥5 µM) according to the dose response curves previously published by others [34][35][36] and according to the dose response observed in the NET cell lines used in this work. These drug doses are seemingly therapeutically relevant considering the high plasma levels of other GSK3α/β inhibitors tolerated such as lithium chloride (0.6-1.2 mM) [37].…”