Thapsigargin-induced apoptosis was prevented by glycogen synthase kinase-3 inhibitors in PC12 cells.
Uncontrolled calcium stress has been linked causally to a variety of neurodegenerative diseases, including ischemia, excitotoxicity and Alzheimer's disease. Thapsigargin, which increases [Ca2+]i, induces apoptotic cell death (chromatin condensation and DNA fragmentation) accompanied by caspase-3 activation in PC12 cells. We examined whether GSK-3 is involved in thapsigargin-induced cell death by using GSK-3 inhibitors in PC12 cells. Cells treated with 0.1 microM thapsigargin for 24h shrank. The injured cells underwent chromatin condensation and nuclear fragmentation, indicating apoptotic cell death. We assayed the effects of selective GSK-3 inhibitors, SB216763, azakenpaullone and alsteropaullone on thapsigargin-induced apoptosis. These inhibitors completely protected cells from thapsigargin-induced apoptosis. Alsterpaullone did not reduce the GRP78 protein expression induced by thapsigargin, suggesting that GSK-3 activation is not involved in induction of GRP78. In addition, GSK-3 inhibitors inhibited caspase-3 activation accompanied by thapsigargin-induced apoptosis. We showed in this report that thapsigargin-induced apoptosis is prevented by GSK-3 inhibitors, suggesting that thapsigargin induces caspase-dependent apoptosis mediated through GSK-3 activation in PC12 cells.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1148, Japan. t-takadera@hokuriku-u.ac.jp
Yoshikawa
Ryoko
R
Ohyashiki
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D018832:Molecular Chaperones / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects*; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP
D001552:Benzazepines; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D006360:Heat-Shock Proteins; D007211:Indoles; D008301:Maleimides; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D019284:Thapsigargin; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C417521:SB 216763; C120793:alsterpaullone