Inhibition of glycogen synthase kinase-3 protects cells from intrinsic but not extrinsic oxidative stress.
Oxidative stress is linked to neuronal dysfunction and death in many diseases. Glycogen synthase kinase-3 often promotes apoptosis, so this investigation tested whether glycogen synthase kinase-3 is linked to oxidative stress-induced apoptosis. Both intrinsic oxidative stress induced by the mitochondrial inhibitor rotenone and extrinsic oxidative stress induced by exogenously added H2O2 activated Bax, caspase-2, and caspase-3 in human neuroblastoma SH-SY5Y cells. Inhibitors of glycogen synthase kinase-3 blocked rotenone-induced, but not H2O2-induced, activation of both caspases, but not Bax activation. Thus, glycogen synthase kinase-3 is an important component of intrinsic oxidative stress-induced apoptosis that acts downstream of mitochondrial Bax activation, and there are substantial differences in the role of glycogen synthase kinase-3, and lithium's effects, in apoptotic signaling induced by intrinsic and extrinsic oxidative stress.
King
Taj D
TD
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, AL 35294-0017, USA.
Jope
Richard S
RS
D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004791:Enzyme Inhibitors; D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D014475:Uncoupling Agents; D051028:bcl-2-Associated X Protein; D012402:Rotenone; D008094:Lithium; D006861:Hydrogen Peroxide; D038362:Glycogen Synthase Kinase 3; D020169:Caspases