Phenethyl isothiocyanate (PEITC) and other structurally related compounds are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear but may involve the regulation of gene expression, such as that by Phase II detoxifying enzymes. To unveil the upstream signaling events that lead to the potential transcriptional activation of genes, we studied the involvement of mitogen-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), and extracellular signal-regulated kinase 1 and 2 cascades, which have been shown to mediate numerous types of extracellular signals. On treatment of human ovarian HeLa cells with PEITC, JNK1 activity was strongly induced in a dose- and time-dependent manner, whereas the activation of extracellular signal-regulated kinase 1 and 2 was not substantial. Furthermore, activation of JNK1 by PEITC was inhibited by pro-oxidants hydrogen peroxide and diamide, although these two pro-oxidants by themselves had opposing effects on JNK1 activity. Pretreatment with an antioxidant, N-acetyl-l-cysteine, had no effects on PEITC activation of JNK1. When comparing the kinetics of JNK1 activation by different isothiocyanates, PEITC elicited a sustained activation, whereas 3-phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate stimulated transient activations. The responsiveness of JNK1 to PEITC, 3-phenylpropyl isothiocyanate, and 4-phenylbutyl isothiocyanate suggests the involvement of JNK1 in the regulation of Phase II detoxifying enzyme gene expression. Furthermore, different patterns of JNK1 induction by these isothiocyanates may contribute to their distinct chemopreventive efficacies in some animal tumor model studies.
This work was supported by NIH Grants R29-GM49172 and R01-ES06887 (A-N. T. K.) and R01-GM49875 and R01-AI38649 (T-H. T.).