GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagy and cell death.
Glycogen synthase kinase 3 beta (GSK-3beta) is constantly active in cells and its activity increases after serum deprivation, indicating that GSK-3beta might play a major role in cell survival under serum starvation. In this study, we attempted to determine how GSK-3beta promotes cell survival after serum depletion. Under full culture conditions (10% FBS), GSK-3beta inhibition with chemical inhibitors or siRNAs failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrotic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3beta-inhibition-induced cell death was in parallel with an extensive autophagic response. Interestingly, blocking the autophagic response switched GSK-3beta-inhibition-induced necrosis to apoptotic cell death. Finally, GSK-3beta inhibition resulted in a remarkable elevation of Bif-1 protein levels, and silencing Bif-1 expression abrogated GSK-3beta-inhibition-induced autophagic response and cell death. Taken together, our study suggests that GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagic response and cell death.
Yang
Jun
J
Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Takahashi
Yoshinori
Y
Cheng
Erdong
E
Liu
Jihong
J
Terranova
Paul F
PF
Zhao
Bin
B
Thrasher
J Brantley
JB
Wang
Hong-Gang
HG
Li
Benyi
B
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008954:Models, Biological; D009336:Necrosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D016895:Culture Media, Serum-Free; D047428:Protein Kinase Inhibitors; C429293:SH3GLB1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3