Yu R, Jiao J J, Duh J L, Tan T H, Kong A N
Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois, Chicago 60612, USA.
Cancer Res. 1996 Jul 1;56(13):2954-9.
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.
苯乙基异硫氰酸酯（PEITC）及其他结构相关化合物在多种动物癌症实验模型中是有效的化学预防剂。这些药剂预防癌症的机制尚不清楚，但可能涉及基因表达的调控，比如II期解毒酶的基因表达调控。为了揭示导致基因潜在转录激活的上游信号事件，我们研究了丝裂原活化蛋白激酶、c-Jun氨基末端激酶1（JNK1）以及细胞外信号调节激酶1和2级联反应的作用，这些已被证明可介导多种类型的细胞外信号。用PEITC处理人卵巢癌细胞系HeLa细胞后，JNK1活性以剂量和时间依赖性方式被强烈诱导，而细胞外信号调节激酶1和2的激活并不明显。此外，PEITC对JNK1的激活被促氧化剂过氧化氢和二酰胺抑制，尽管这两种促氧化剂自身对JNK1活性有相反的影响。用抗氧化剂N-乙酰-L-半胱氨酸预处理对PEITC激活JNK1没有影响。比较不同异硫氰酸酯激活JNK1的动力学时，PEITC引起持续激活，而3-苯丙基异硫氰酸酯和4-苯丁基异硫氰酸酯刺激短暂激活。JNK1对PEITC、3-苯丙基异硫氰酸酯和4-苯丁基异硫氰酸酯的反应表明JNK1参与II期解毒酶基因表达的调控。此外，这些异硫氰酸酯诱导JNK1的不同模式可能在一些动物肿瘤模型研究中导致它们具有不同的化学预防效果。
