Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates.
Isothiocyanates have strong chemopreventive properties against many carcinogen-induced cancers in experimental animal models. Here, we report that phenylmethyl isocyacyanate (PMITC) and phenylethyl isothiocyanate (PEITC) induced sustained c-Jun N-terminal kinase (JNK) activation in a dose-dependent manner. The sustained JNK activation caused by isothiocyanates was associated with apoptosis induction in various cell types. An inhibitor of the caspase/interleukin-1 beta-converting enzyme blocked isothiocyanate-induced apoptosis without inhibiting the JNK activation, which suggests that JNK activation by isothiocyanates is an event that is independent or upstream of the activation of caspase/interleukin-1 beta-converting enzyme proteases. PEITC-induced apoptosis was suppressed by interfering with the JNK pathway with a dominant-negative mutant of JNK1 or MEKK1 (JNK1(APF) and MEKK1 (KR), respectively), implying that the JNK pathway is required for apoptotic signaling. Isothiocyanate-induced JNK activation was blocked by the antioxidants 2-mercaptoethanol and N-acetyl-L-cysteine, suggesting that the death signaling was triggered by oxidative stress. Overexpression of Bcl-2 suppressed PEITC-induced JNK activation. In addition, Bcl-2 and Bcl-xL suppressed PEITC-induced apoptosis, but failed to protect cells from death induced by overexpression of activated JNK1. These results suggest that Bcl-2 and Bcl-xL are upstream of JNK. Taken together, our results indicate (i) that JNK mediates PMITC- and PEITC-induced apoptosis and (ii) that PMITC and PEITC may have chemotherapeutic functions besides their chemopreventive functions.
Chen
Y R
YR
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wang
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W
Kong
A N
AN
Tan
T H
TH
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis*; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; C093849:3-phenylpropyl isothiocyanate; C058305:phenethyl isothiocyanate; D000444:Aldehyde Dehydrogenase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D020170:Caspase 1