Arachidonic acid converts the glutathione depletion-induced apoptosis to necrosis by promoting lipid peroxidation and reducing caspase-3 activity in rat glioma cells.
Intracellular glutathione (GSH) depletion induced by buthionine sulfoximine (BSO) caused cell death that seemed to be apoptosis in C6 rat glioma cells. Arachidonic acid (AA) promoted BSO-induced cell death by accumulating reactive oxygen species (ROS) or hydroperoxides. AA inhibited caspase-3 activation and internucleosomal DNA fragmentation during the BSO-induced GSH depletion. Furthermore, AA reduced intracellular ATP content, induced dysfunction of mitochondrial membrane and enhanced 8-hydroxy-2'-deoxyguanosine (8-OH-dG) production. There was significant increase of 12-lipoxygenase activity in the presence of AA under the BSO-induced GSH depletion in C6 cells. These results suggest that AA promotes cell death by changing to necrosis from apoptosis through lipid peroxidation initiated by lipid hydroperoxides produced by 12-lipoxygenase under the GSH depletion in C6 cells. Some ROS such as hydroperoxide produced by unknown pathway make hydroxy radicals and induce 8-OH-dG formation in the cells. The conversion of apoptosis to necrosis may be a possible event under GSH depleted conditions.
Higuchi
Yoshihiro
Y
Department of Molecular Pharmacology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. higuchiy@med.kanazawa-u.ac.jp
Yoshimoto
Tanihiro
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D004789:Enzyme Activation; D005910:Glioma / Q000201:enzymology* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008564:Membrane Potentials; D009336:Necrosis; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D013997:Time Factors; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D001092:Arachidonate 12-Lipoxygenase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D010100:Oxygen