Involvement of PI3K/AKT/GSK3ß pathway in tetrandrine-induced G1 arrest and apoptosis

Abstract

It has been reported that tetrandrine induces cell cycle arrest and apoptosis in human cancer cells. In the present study, we investigated the role of PI3K/AKT/GSK3ß pathway in tetrandrine- induced G1 arrest and apoptosis. In HT-29 cells, tetrandrine induced dephosphorylation of AKT, activation and nuclear translocation of GSK3ß as well as up-regulation of p27kip1. Activation of GSK3ß via AKT inhibitoion induced by tetrandrine resulted in enhanced phosphorylation and proteolysis of cyclin D1, activation of caspase 3 and subsequent cleavage of PARP. Selective GSK3ß inhibitiors and GSK3ß siRNA attenuated tetrandrine-induced G1 arrest and apoptosis. Similar to tetrandrine, transfection of wild-type GSK3ß led to G1 arrest and apoptosis via down-regulation of cyclin D1 and cleavage of PARP. These findings suggest that tetrandrine induces G1 arrest and apoptosis through PI3K/AKT/GSK3ß pathway and identify GSK3ß as an important mediator in the processes.