Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway
Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway
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DOI：
10.1016/j.bcp.2008.02.016
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发表时间：
2008-05-15
影响因子：
5.8
通讯作者：
Lee, Yong J.
中科院分区：
文献类型：
--
作者：
Kim, Young-Ho;Lee, Dae-Hee;Lee, Yong J.
槲皮素和TRAIL的联合治疗诱导细胞毒性，并增强膜联蛋白V染色和聚（ADP-核糖）聚合酶（PARP）切割人前列腺癌细胞系DU-145和PC-3。这些凋亡指标是由caspase-8、-9和-3的激活引起的。虽然FLIPs，cIAP 1，cIAP 2和Bcl-2家族的表达水平在槲皮素处理的细胞中没有改变，但发生了生存素的显著下调。通过siRNA敲低生存素显著增加TRAIL诱导的细胞凋亡。我们推测槲皮素诱导的MAPK（ERK，p38，JNK）的激活是导致Survivin基因表达下调的原因。为了验证这一假设，我们选择性地抑制MAPK与槲皮素治疗过程中。我们的数据表明，ERK抑制剂（PD 98059），而不是p38 MAPK（SB 203580）或JNK（SP 600125），在槲皮素处理过程中，显着维持细胞内生存素的水平。有趣的是，PD 98059还阻止了槲皮素诱导的组蛋白H3的脱乙酰化。Survivin启动子活性检测结果表明，Sp1转录因子与Survivin启动子区结合，槲皮素通过组蛋白H3的脱乙酰化作用抑制其结合活性。槲皮素诱导的ERK-MSK 1信号转导通路的激活可能是负责组蛋白H3的去乙酰化。综上所述，我们的研究结果表明，槲皮素增强TRAIL诱导的细胞凋亡抑制生存素的表达，通过ERK-MSK 1介导的H3的脱乙酰化。(C)2008年爱思唯尔公司All rights reserved.
Combined treatment with quercetin and TRAIL induced cytotoxicity and enhanced annexin V staining and poly (ADP-ribose) polymerase (PARP) cleavage in human prostate cancer cell lines DU-145 and PC-3. These indicators of apoptosis resulted from the activation of caspase-8, -9, and -3. Although the expression levels of FLIPs, cIAP1, cIAP2, and the Bcl-2 family were not changed in quercetin-treated cells, significant downregulation of survivin occurred. Knockdown survivin by siRNA significantly increased TRAIL-induced apoptosis. We hypothesized that quercetin-induced activation of MAPK (ERK, p38, JNK) is responsible for downregulation of survivin gene expression. To test this hypothesis, we selectively inhibited MAPK during treatment with quercetin. Our data demonstrated that inhibitor of ERK (PD98059), but not p38 MAPK (SB203580) or JNK (SP600125), significantly maintained the intracellular level of survivin during treatment with quercetin. Interestingly, PD98059 also prevented quercetin-induced deacetylation of histone H3. Data from survivin promoter activity assay suggest that the Sp1 transcription factor binds to the survivin promoter region and quercetin inhibits its binding activity through deacetylation of histone H3. Quercetin-induced activation of the ERK-MSK1 signal transduction pathway may be responsible for deacetylation of histone H3. Taken together, our findings suggest that quercetin enhances TRAIL induced apoptosis by inhibition of survivin expression, through ERK-MSK1-mediated deacetylation of H3. (C) 2008 Elsevier Inc. All rights reserved.