Involvement of PI3K/AKT/GSK3beta pathway in tetrandrine-induced G1 arrest and apoptosis.

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/GSK3beta pathway in tetrandrine- induced G(1) arrest and apoptosis. In HT-29 cells, tetrandrine induced dephosphorylation of AKT, activation and nuclear translocation of GSK3beta as well as upregulation of p27(kip1). Activation of GSK3beta via AKT inhibitoion induced by tetrandrine resulted in enhanced phosphorylation and proteolysis of cyclin D(1), activation of caspase 3 and subsequent cleavage of PARP. Selective GSK3beta inhibitiors and GSK3beta siRNA attenuated tetrandrine-induced G(1) arrest and apoptosis. Similar to tetrandrine, transfection of wild-type GSK3beta led to G(1) arrest and apoptosis via downregulation of cyclin D(1) and cleavage of PARP. These findings suggest that tetrandrine induces G(1) arrest and apoptosis through PI3K/AKT/GSK3beta pathway and identify GSK3beta as an important mediator in the processes.