Molecular Mechanisms of c-Jun N-terminal Kinase-mediated Apoptosis Induced by Anticarcinogenic Isothiocyanates

• Published in: The Journal of biological chemistry Vol. 273; no. 3; pp. 1769 - 1775
• Main Authors: Chen, Yi-Rong, Wang, Wenfu, Kong, A.-N. Tony, Tan, Tse-Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-01-1998; American Society for Biochemistry and Molecular Biology
• Subjects: Aldehyde Dehydrogenase - antagonists & inhibitors; Anticarcinogenic Agents - pharmacology; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinases - biosynthesis; Caspase 1; Cysteine Endopeptidases - metabolism; Dose-Response Relationship, Drug; Enzyme Induction; Enzyme Inhibitors - pharmacology; Humans; Isothiocyanates - pharmacology; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Mitogen-Activated Protein Kinases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.3.1769

Isothiocyanates have strong chemopreventive properties against many carcinogen-induced cancers in experimental animal models. Here, we report that phenylmethyl isocyacyanate (PMITC) and phenylethyl isothio- cyanate (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-1β-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-1β-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 andN-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.