Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells
Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells
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DOI：
10.3324/haematol.2011.046466
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Micheau, Olivier
中科院分区：
文献类型：
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作者：
Jacquemin, Guillaume;Granci, Virginie;Micheau, Olivier
背景非霍奇金B细胞淋巴瘤约占B细胞淋巴瘤的70%。虽然其发病率在世界范围内急剧增加，但由于常规疗法无效，该疾病仍然与高发病率相关，迫切需要新的治疗方法。通过Hoescht、流式细胞术、Western印迹、qPCR、流式细胞术、免疫印迹、免疫荧光和免疫荧光等方法，通过使用siRNA或线粒体途径的药理学抑制剂，并通过免疫沉淀，然后通过翻译后修饰分析。结果表明，槲皮素，一种天然类黄酮，恢复TRAIL诱导的细胞死亡的抗性转化滤泡性淋巴瘤B细胞系，尽管由于染色体易位t（14;18）导致Bcl-2表达水平高。槲皮素通过诱导Mcl-1的蛋白酶体降解和通过在mRNA水平抑制生存素表达来挽救线粒体活化，而与p53无关。TRAIL途径的恢复需要Bax和巴克，但独立于增强的TRAIL DISC formation.ConclusionsWe表明，槲皮素的生存素和Mcl-1表达的失活是足以恢复TRAIL的敏感性在耐药的非霍奇金淋巴瘤B细胞。因此，我们的研究结果表明，槲皮素与TRAIL治疗相结合，可能是有用的非霍奇金淋巴瘤的治疗。
BackgroundNon-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas.Design and MethodsMolecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis.ResultsResults demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation.ConclusionsWe demonstrate that inactivation of survivin and Mcl-1 expression by quercetin is sufficient to restore TRAIL sensitivity in resistant non-Hodgkin's lymphoma B cells. Our results suggest, therefore, that combining quercetin with TRAIL treatments may be useful in the treatment of non-Hodgkin's lymphoma.