Resveratrol analog, 3,4,5,4′-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts
Resveratrol analog, 3,4,5,4′-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts
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DOI：
10.1093/carcin/22.2.321
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发表时间：
2001-02-01
期刊：
影响因子：
4.7
通讯作者：
Chen, KY
中科院分区：
文献类型：
--
作者：
Lu, JB;Ho, CT;Chen, KY
白藜芦醇，一种在葡萄和其他植物中发现的三羟基苯乙烯，已被证明在抑制多阶段癌变方面具有活性。以白藜芦醇为原型，合成了多羟基和多甲氧基二苯乙烯，并在正常和转化的人体细胞中测试了它们的抗增殖作用。本研究表明，白藜芦醇类似物之一3,4,5,4'-四羟基苯乙烯（R-4）在10 muM时特异性抑制SV40病毒转化WI38细胞（WI38VA）的生长，但在更高浓度下对正常WI38细胞没有影响。R-4也显著诱导WI38VA细胞凋亡，但对WI38细胞无明显影响。RNase保护实验显示，R-4能显著诱导WI38VA细胞中p53、GADD45和Bax基因的表达，同时抑制bcl-2基因的表达，但在WI38细胞中无明显作用。p53 DNA结合活性的大幅增加和Bax启动子结合复合体中p53的存在表明，p53在转化细胞中负责R-4诱导的Bax基因表达。在R-4作用4 h内，WI38和WI38VA细胞中Bax与bcl-2蛋白的比值分别为0.1和105，差异达3个数量级。R-4在显著诱导p53/Bax促凋亡基因的同时，也抑制了WI38VA细胞中Cox-2的表达。综上所述，我们的研究表明，R-4诱导转化细胞中p53基因的表达可能在转化细胞的差异生长抑制和凋亡中起关键作用。
Resveratrol, a trihydroxystilbene found in grapes and other plants, has been shown to be active in inhibiting multistage carcinogenesis. Using resveratrol as a prototype, we have synthesized a number of polyhydroxy- and polymethoxystilbenes and tested their anti-proliferative effect in normal and transformed human cells. Here we show that one of the resveratrol analogs, 3,4,5,4'-tetrahydroxystilbene (R-4), specifically inhibited the growth of SV40 virally transformed WI38 cells (WI38VA) at 10 muM, but had no effect on normal WI38 cells at even higher concentrations. R-4 also prominently induced apoptosis in WI38VA cells, but not in WI38 cells. RNase protection assay showed that R-4 significantly induced the expression of p53, GADD45 and Bax genes and concomitantly suppressed the expression of bcl-2 gene in WI38VA, but not in WI38 cells. A large increase in p53 DNA binding activity and the presence of p53 in the Bax promoter binding complex suggested that p53 was responsible for the Bax gene expression induced by R-4 in transformed cells. Within 4 h of treatment with R-4, the Bax to bcl-2 protein ratio in WI38 and WI38VA cells was, respectively, 0.1 and 105, a difference of three orders of magnitude. While R-4 prominently induced the p53/Bax pro-apoptotic genes, it also concomitantly suppressed the expression of Cox-2 in WI38VA cells, Taken together, our study suggests that the induction of p53 gene by R-4 in transformed cells may play a key role in the differential growth inhibition and apoptosis of transformed cells.