TY - JOUR T1 - Enhancement of Metabolic Oxidative Stress-Induced Cytotoxicity by the Thioredoxin Inhibitor 1-Methylpropyl 2-Imidazolyl Disulfide Is Mediated through the ASK1-SEK1-JNK1 Pathway JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1409 LP - 1417 DO - 10.1124/mol.62.6.1409 VL - 62 IS - 6 AU - Yong J. Lee AU - Jin H. Kim AU - Jun Chen AU - Jae J. Song Y1 - 2002/12/01 UR - http://molpharm.aspetjournals.org/content/62/6/1409.abstract N2 - 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 μM). 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. ER -