Oroxylin A Reversed Fibronectin-Induced Glioma Insensitivity To Temozolomide By Suppressing Ip(3)R1/Akt/Beta-Catenin Pathway

Aims: Cell adhesion mediated-drug resistance (CAM-DR) is one of main reasons for the limitation to chemotherapy, but the underlying mechanism remains unclear in glioma. In this study, we investigated the mechanism of CAM-DR induced by Fibronectin (Fn). Besides, we studied the reversal effect of Oroxylin A, a natural flavonoid extracted from Scutellaria radix, on Temozolomide (TMZ) insensitivity of glioma cells.Main methods: Human Fn protein was used to mimic cell adhesion model and investigate its effect on the insensitivity of glioma cells to TMZ. Moreover, Oroxylin A was studied regarding its reversal effect on TMZ insensitivity of glioma via multiple molecular biological methods such as MIT, cell apoptosis assay, siRNA transfection, western blot, immunofluorescence assay.Key findings: Fn could decrease the apoptosis-inducing effect of TMZ and led to the CAM-DR in glioma cells. Further studies showed that up-regulations of IP(3)R1 and intracellular Ca2+ level induced the activation of AKT kinase which increased the phosphorylation of GSK-3 beta and subsequently caused the entry of beta-catenin into the nucleus. Knocking down IP 3 R1 significantly improved the sensitivity of glioma cells to TMZ. Meanwhile, after treatment with low-toxic concentration of Oroxylin A, the apoptosis induced by TMZ under Fn condition increased dramatically. Furthermore, our results revealed that Oroxylin A markedly inhibited the expression of IP(3)R1 and the activation of AKT/beta-catenin pathway.Significance: Oroxylin A could reverse the insensitivity of TMZ via suppressing IP(3)R1/AKT/beta-catenin pathway and it might be helpful for enhancing the anti-cancer effect of TMZ in glioma.