Enhancement of metabolic oxidative stress-induced cytotoxicity by the thioredoxin inhibitor 1-methylpropyl 2-imidazolyl disulfide is mediated through the ASK1-SEK1-JNK1 pathway.
We observed previously that glucose deprivation induces cytotoxicity, increases the intracellular levels of hydroperoxide, and activates the stress-activated protein kinase (SEK) pathway. In this study, we hypothesized that 1-methylpropyl 2-imidazolyl disulfide (IV-2), a thioredoxin (TRX) inhibitor, augments glucose deprivation-induced cytotoxicity by promoting c-Jun N-terminal kinase (JNK) activation. Human prostatic carcinoma DU-145 cells were exposed to glucose-free medium containing various concentrations of IV-2 (10-50 microM). Glucose deprivation alone or IV-2 alone induced minimal cytotoxicity within 7 h. However, the combination of glucose deprivation and IV-2 increased cell death in a dose-dependent manner. The cytotoxicity was suppressed by treatment with an antioxidant, N-acetyl-L-cysteine or overexpressing TRX. The combined glucose deprivation and IV-2 treatment also promoted glucose deprivation-induced JNK1 activation by disrupting the interaction between TRX and apoptosis signal-regulating kinase 1 (ASK1). Overexpression of the JNK1 dominant-negative mutant inhibited the activation of the SEK pathway and protected cells from glucose deprivation and IV-2-induced cytotoxicity. Therefore, IV-2 enhances glucose deprivation-induced cytotoxicity by promoting glucose deprivation-induced activation of the ASK1-SEK1-JNK1 pathway.
Lee
Yong J
YJ
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. leeyj@msx.upmc.edu
Kim
Jin H
JH
Chen
Jun
J
Song
Jae J
JJ
D000111:Acetylcysteine / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004220:Disulfides / Q000494:pharmacology*; D004347:Drug Interactions; D004789:Enzyme Activation; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D013879:Thioredoxins / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004220:Disulfides; D007093:Imidazoles; D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide; D002374:Catalase; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D005947:Glucose; D000111:Acetylcysteine