Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates
Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates
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DOI：
10.1074/jbc.273.3.1769
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发表时间：
1998-01-16
影响因子：
4.8
通讯作者：
Tan, TH
中科院分区：
文献类型：
--
作者：
Chen, YR;Wang, WF;Tan, TH
在实验动物模型中，异硫氰酸酯对许多致癌物诱导的癌症具有很强的化学预防作用。在此，我们报道了苯甲基异氰酸酯(PMITC)和苯乙基异硫氰酸酯(PEITC)以剂量依赖的方式诱导c-jun氨基末端激酶(JNK)的持续激活。异硫氰酸酯诱导的JNK持续激活与诱导多种细胞类型的细胞凋亡有关，caspase/IL-1β转换酶的抑制剂阻断了异硫氰酸酯诱导的细胞凋亡，但不抑制JNK的激活，这表明异硫氰酸酯激活JNK是一个独立于caspase/IL-1β转换酶激活的事件或上游事件。通过用JNK1或MEKK1的显性负突变(分别为JNK1(APF)和MEKK1(KR))干扰JNK通路，抑制了PEITC诱导的细胞凋亡，这表明JNK通路是细胞凋亡信号转导所必需的。异硫氰酸盐诱导的JNK活化可被抗氧化剂2-巯基乙醇和N-乙酰-L半胱氨酸阻断，提示死亡信号是由氧化应激触发的。Bcl2过表达可抑制PEITC诱导的JNK活化。此外，Bcl2和Bclx(L)可抑制PEITC诱导的细胞凋亡，但不能保护激活的JNK1过表达所致的细胞死亡。这些结果表明，Bcl2和Bclx(L)位于JNK的上游。综上所述，我们的结果表明：(1)JNK介导了PMITC和PEITC诱导的细胞凋亡；(2)PMITC和PEITC除了具有化学预防功能外，可能还具有化疗功能。
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-x(L) 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-x(L) 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.