PHENETHYL ISOTHIOCYANATE, A NATURAL CHEMOPREVENTIVE AGENT, ACTIVATES C-JUN N-TERMINAL KINASE-1

Phenethyl isothiocyanate (PEITC) and other structurally related compou nds are potent chemopreventive agents in a number of experimental mode ls 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 activatio n of genes, we studied the involvement of mitogen-activated protein ki nase, c-Jun N-terminal kinase 1 (JNK1), and extracellular signal-regul ated kinase 1 and 2 cascades, which have been shown to mediate numerou s types of extracellular signals. On treatment of human ovarian HeLa c ells with PEITC, JNK1 activity was strongly induced in a dose- and tim e-dependent manner, whereas the activation of extracellular signal-reg ulated kinase 1 and 2 was not substantial. Furthermore, activation of JNK1 by PEITC was inhibited by pro-oxidants hydrogen peroxide and diam ide, although these two pro-oxidants by themselves had opposing effect s on JNK1 activity. Pretreatment tvith an antioxidant, N-acetyl-L-cyst eine, had no effects on PEITC activation of JNK1. When comparing the k inetics of JNK1 activation by different isothiocyanates, PEITC elicite d a sustained activation, whereas 3-phenylpropyl isothiocyanate and 4- phenylbutyl isothiocyanate stimulated transient activations. The respo nsiveness of JNK1 to PEITC, 3-phenylpropyl isothiocyanate, and 4-pheny lbutyl isothiocyanate suggests the involvement of JNK1 in the regulati on of Phase II detoxifying enzyme gene expression. Furthermore, differ ent patterns of JNK1 induction by these isothiocyanates may contribute to their distinct chemopreventive efficacies in some animal tumor mod el studies.