| Glycogen synthase kinase 3β(GSK-3β) belongs to a family of conserved serine/threonine kinases present in all eukaryotic groups. It was shown to function in a wide range of biological processes, including cell cycle progression, gene transcription, apoptosis, cellular metabolism, cell movement and tumorigenesis. Emerging evidence revealed that GSK-3βis constantly active in cells and its activity increases significantly after serum deprivation, indicating that GSK-3βmay play a major role in cell death/survival under serum starvation. In the present study, we attempted to understand how GSK-3βcontrols cell death/survival after serum depletion. Under full culture conditions(10% FBS), GSK-3βinhibition with chemical inhibitors or siRNA failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrostic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3β-inhibition-induced cell death was parallel with an extensive autophagic response. Interestingly, blocking the autophagic response did not block GSK-3β-inhibition-induced cell death but switched it from necrosis to apoptotic cell death, which was associated with a Bax conformational change. Most importantly, knocking down bif-1 expression abolished GSK-3β-inhibition-induced autophagic response and cell death, as well as lysosomal membrane permeabilization, indicating that bif-1 is requires for the GSK-3β-inhibition-induced cytotoxic effect. Finally, GSK-3βsuppression increased bif-1 promoter activity, and subsequently up-regulated bif-1 expression, enhanced bif-1 interaction with Beclin-1/vps34 complex that is a key component in the autophagic process. Take together, our data suggest that GSK-3βcontrols cell death/survival by modulating of bif-1 dependent autophagic reponse and bif-1 dependent bax conformational change.
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