Regulation of AKT phosphorylation by GSK3 and PTEN to control chemoresistance in breast cancer

BackgroundPhosphorylated AKT is highly expressed or overexpressed in chemoresistant tumor samples. However, the precise molecular mechanism involved in AKT phosphorylation-related chemoresistance in breast cancer is still elusive. The present research was designed to estimate the effect of AKT phosphorylation on cell viability and chemoresistance in breast cancer.MethodsWe utilized MCF-7 and MDA-MB468 human breast cancer cell lines and developed multidrug-resistant MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells. Immunofluorescence analysis and Western blotting were employed to test the level of glycogen synthase kinase 3 beta (GSK3), phosphorylated phosphatase and tension homologue (p-PTEN) and phosphorylated AKT (p-AKT) in MCF-7/MDR and MDA-MB468 cells. Xenograft assays in nude mice were performed with MCF-7/MDR cells to verify chemoresistance and the signaling pathway upstream of phosphatidylinositide 3-kinase (PI3K)/AKT.ResultsAn increase in GSK3, p-PTEN and p-AKT expression was strongly induced in MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells, and augmented GSK3 phosphorylation and PTEN inactivation enhanced AKT signaling. The elevation in GSK3, p-PTEN and p-AKT was associated with cell viability based on a CCK-8 assay. The results of in vivo and in vitro assays indicated that GSK3 knockdown with lentiviral shRNA (shRNA-GSK3) promoted apoptosis and suppressed the migration of cisplatin-resistant MCF-7/MDR cells, while these effects were reversed by activating p-AKT with the PTEN inhibitor bpV(pic).ConclusionsAKT phosphorylation mediated by GSK3 and PTEN were correlated with cell viability, migration and apoptosis, which may promote chemoresistance in breast cancer. Furthermore, GSK3 can regulate cell viability through the PTEN/PI3K/AKT signaling pathway and induce chemoresistance, serving as a valuable molecular strategy for breast cancer therapy.