Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells.
Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells.
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白藜芦醇触发促凋亡的内质网应激反应，并抑制人类多发性骨髓瘤细胞中的促生物性XBP1信号传导。
DOI：
10.1016/j.exphem.2011.06.007
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发表时间：
2011-10
影响因子：
2.6
通讯作者：
Ouyang, Hongjiao
中科院分区：
文献类型：
--
作者：
Wang, Feng-Ming;Galson, Deborah L.;Roodman, G. David;Ouyang, Hongjiao
白藜芦醇，反式-3，4 '，5，-三羟基芪，抑制多发性骨髓瘤（MM）。内质网（ER）应激反应组分IRE 1 α/XBP 1轴在MM发病机制中是必不可少的。我们研究了白藜芦醇对人MM细胞IRE 1 α/XBP 1轴的分子作用。利用人MM细胞系ANBL-6、OPM 2和MM. 1 S来确定用白藜芦醇处理后的分子信号传导事件。Western blot和逆转录聚合酶链反应检测IRE 1 α/XBP 1轴的激活情况。通过荧光素酶测定评估白藜芦醇对剪接的XBP 1的转录活性的影响。染色质免疫沉淀法（ChIP）检测白藜芦醇对MM细胞中XBP 1 DNA结合活性的影响。白藜芦醇激活MM细胞中的IRE 1 α，如通过MBP 1 mRNA剪接和IRE 1 α及其下游激酶JNK的磷酸化所证明的。这些反应与白藜芦醇诱导的MM细胞的细胞毒性有关。白藜芦醇选择性地抑制XBP 1的转录活性，同时刺激ER应激反应中受非IRE 1/XBP 1轴调控的分子的基因表达。荧光素酶分析表明，白藜芦醇通过sirtuin 1（SIRT 1），白藜芦醇的下游分子靶点抑制XBP 1 s的转录活性。ChIP研究表明，白藜芦醇降低了XBP 1的DNA结合能力，并增加了SIRT 1在XBP 1启动子中XBP 1结合区域的富集。白藜芦醇通过损害促存活XBP 1信号传导和激活促凋亡ER应激反应的机制对人MM细胞发挥其化疗作用。
Resveratrol, trans-3, 4’, 5,-trihydroxystilbene, suppresses multiple myeloma (MM). The endoplasmic reticulum (ER) stress response component IRE1α/XBP1 axis is essential for MM pathogenesis. We investigated the molecular action of resveratrol on IRE1α/XBP1 axis in human MM cells. Human MM cell lines ANBL-6, OPM2, and MM.1S were utilized to determine the molecular signaling events following the treatment with resveratrol. The stimulation of IRE1α/XBP1 axis was analyzed by Western blot and reverse transcription polymerase chain reaction. The effect of resveratrol on the transcriptional activity of spliced XBP1 was assessed by luciferase assays. Chromatin immunoprecipitation (ChIP) was performed to determine the effects of resveratrol on the DNA binding activity of XBP1 in MM cells. Resveratrol activated IRE1α as evidenced by XBP1 mRNA splicing and the phosphorylation of both IRE1α and its downstream kinase JNK in MM cells. These responses were associated with resveratrol-induced cytotoxicity of MM cells. Resveratrol selectively suppressed the transcriptional activity of XBP1s while it stimulated gene expression of the molecules that are regulated by non-IRE1/XBP1 axis of the ER stress response. Luciferase assays indicated that resveratrol suppressed the transcriptional activity of XBP1s through sirtuin 1 (SIRT1), a downstream molecular target of resveratrol. ChIP studies revealed that resveratrol decreased the DNA binding capacity of XBP1 and increased the enrichment of SIRT1 at the XBP1 binding region in the XBP1 promoter. Resveratrol exerts its chemotherapeutic effect on human MM cells through mechanisms involving the impairment of the pro-survival XBP1 signaling and the activation of pro-apoptotic ER stress response.
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DOI：
10.1042/bj20101293
发表时间：
2011-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Wang FM;Chen YJ;Ouyang HJ
通讯作者：
Ouyang HJ
影响因子：
--
作者：
Shajahan AN;Riggins RB;Clarke R
通讯作者：
Clarke R
影响因子：
30.8
作者：
Kakiuchi, C;Iwamoto, K;Kato, T
通讯作者：
Kato, T
影响因子：
3.7
作者：
Pereira, Ethel R.;Liao, Nan;Hendershot, Linda M.
通讯作者：
Hendershot, Linda M.
影响因子：
20.3
作者：
Papandreou, Ioanna;Denko, Nicholas C.;Koong, Albert C.
通讯作者：
Koong, Albert C.