Chen Y R, Wang W, Kong A N, Tan T H
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
J Biol Chem. 1998 Jan 16;273(3):1769-75. 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 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 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.
异硫氰酸酯在实验动物模型中对多种致癌物诱导的癌症具有强大的化学预防特性。在此，我们报告苯甲基异氰酸酯（PMITC）和苯乙基异硫氰酸酯（PEITC）以剂量依赖的方式诱导持续的c-Jun氨基末端激酶（JNK）激活。异硫氰酸酯引起的持续JNK激活与多种细胞类型中的凋亡诱导相关。半胱天冬酶/白细胞介素-1β转化酶的抑制剂可阻断异硫氰酸酯诱导的凋亡，而不抑制JNK激活，这表明异硫氰酸酯引起的JNK激活是一个独立于半胱天冬酶/白细胞介素-1β转化酶蛋白酶激活或在其上游的事件。用JNK1或MEKK1的显性负突变体（分别为JNK1(APF)和MEKK1(KR)）干扰JNK途径可抑制PEITC诱导的凋亡，这意味着JNK途径是凋亡信号传导所必需的。异硫氰酸酯诱导的JNK激活被抗氧化剂2-巯基乙醇和N-乙酰-L-半胱氨酸阻断，表明死亡信号是由氧化应激触发的。Bcl-2的过表达抑制了PEITC诱导的JNK激活。此外，Bcl-2和Bcl-xL抑制了PEITC诱导的凋亡，但未能保护细胞免受激活的JNK1过表达诱导的死亡。这些结果表明Bcl-2和Bcl-xL在JNK的上游。综上所述，我们的结果表明：（i）JNK介导PMITC和PEITC诱导的凋亡；（ii）PMITC和PEITC除了具有化学预防功能外，可能还具有化疗功能。
