Glycogen synthase kinase-3β facilitates staurosporine- and heat shock-induced apoptosis -: Protection by lithium

The potential role of glycogen synthase kinase-3 beta in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3 beta to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis, Inhibition of glycogen synthase kinase-3 beta by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3 beta. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3 beta-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3 beta facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3 beta may contribute to proapoptotic-signaling activity, that inhibition of glycogen synthase kinase-3 beta can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3 beta.