Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates.

The Journal of Biological Chemistry
Y R ChenT H Tan

Abstract

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 ...Continue Reading

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Citations

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