Pullar Juliet M, Thomson Susan J, King Monica J, Turnbull Christopher I, Midwinter Robyn G, Hampton Mark B
Free Radical Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, New Zealand.
Carcinogenesis. 2004 May;25(5):765-72. doi: 10.1093/carcin/bgh063. Epub 2004 Jan 16.
The chemopreventive properties of the isothiocyanates have been attributed to their ability to inhibit phase I enzymes that activate procarcinogens, induce phase II protective enzymes and trigger apoptosis in transformed cells. In this study we provide evidence for a new mechanism of chemoprevention, wherein sublethal doses of phenethyl isothiocyanate (PEITC) sensitize cells to Fas-mediated apoptosis. The phenomenon was observed in the Fas-resistant T24 bladder carcinoma cell line and in Jurkat T cells overexpressing the anti-apoptotic protein Bcl-2. Caspase-3-like activity was increased up to 20-fold of that observed with either PEITC or anti-Fas antibody alone. While PEITC activated ERK, JNK and p38, inhibitors of these MAP kinases did not block apoptosis. PEITC transiently depleted cellular glutathione, providing a putative mechanism for sensitizing the cells to apoptosis. However, lowering glutathione with buthionine sulfoximine did not mimic the effect of PEITC. Instead, we propose that PEITC promotes apoptosis by directly modifying intracellular thiol proteins. The ability of PEITC to sensitize cells to receptor-mediated apoptosis provides an additional mechanism to explain its chemopreventive properties.
异硫氰酸盐的化学预防特性归因于它们抑制激活前致癌物的I相酶、诱导II相保护酶以及触发转化细胞凋亡的能力。在本研究中，我们提供了一种新的化学预防机制的证据，其中亚致死剂量的苯乙基异硫氰酸盐（PEITC）使细胞对Fas介导的凋亡敏感。在Fas抗性T24膀胱癌细胞系和过表达抗凋亡蛋白Bcl-2的Jurkat T细胞中观察到了这种现象。半胱天冬酶-3样活性比单独使用PEITC或抗Fas抗体时观察到的活性增加了20倍。虽然PEITC激活了ERK、JNK和p38，但这些丝裂原活化蛋白激酶的抑制剂并未阻断凋亡。PEITC短暂耗尽细胞内谷胱甘肽，为使细胞对凋亡敏感提供了一种假定机制。然而，用丁硫氨酸亚砜胺降低谷胱甘肽水平并不能模拟PEITC的作用。相反，我们提出PEITC通过直接修饰细胞内硫醇蛋白来促进凋亡。PEITC使细胞对受体介导的凋亡敏感的能力为解释其化学预防特性提供了另一种机制。
