title: The proteasome inhibitor MG-132 induces AIF nuclear translocation through down-regulation of ERK and Akt/mTOR pathway.
abstract: Anticancer activity of proteasome inhibitors has been demonstrated in various cancer cell types. However, mechanisms by which they exert anticancer action were not fully understood. The present study was undertaken to examine the effect of the proteasome inhibitor MG-132 and the underlying mechanism in glioma cells. MG-132 caused alterations in mitochondrial membrane potential and apoptosis-inducing factor (AIF) nuclear translocation. MG-132 induced reduction in ERK and Akt activation. The transient transfection of constitutively active forms of MEK, an upstream of ERK, and Akt blocked the MG-132-induced cell death. Similarly to down-regulation of Akt, expression levels of mTOR were inhibited by MG-132. Addition of rapamycin, an inhibitor of mTOR, caused stimulation of the MG-132-induced cell death. There were no significant changes in levels of XIAP, survivin, and Bax. Overexpression of constitutively active forms of MEK and Akt blocked the MG-132-induced AIF nuclear translocation. These findings indicate that MG-132 induces AIF nuclear translocation through down-regulation of ERK and Akt/mTOR pathways. These data suggest that proteasome inhibitors may serve as potential therapeutic agents for malignant human gliomas.
authors.affiliation: Department of Neurosurgery, College of Medicine, Pusan National University, Pusan 602-739, Korea.
authors.forename: Jun Kyeung
authors.initials: JK
authors.lastname: Ko
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Choi
authors.forename: Yong Keun
authors.initials: YK
authors.lastname: Kim
authors.forename: Chae Hwa
authors.initials: CH
authors.lastname: Kwon
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007976:Leupeptins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde