Vernodalol enhances TRAIL‐induced apoptosis in diffuse large B‐cell lymphoma cells
Vernodalol enhances TRAIL‐induced apoptosis in diffuse large B‐cell lymphoma cells
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DOI：
10.1002/mc.22672
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发表时间：
2017-05
影响因子：
4.6
通讯作者：
Wen-jun Wu;Yang Yang-Yang;G. Deng;Liang Ma;G. Wei;G. Zheng;Xiaoyan Han;D. He;Yi Zhao;
中科院分区：
文献类型：
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作者：
Wen-jun Wu;Yang Yang-Yang;G. Deng;Liang Ma;G. Wei;G. Zheng;Xiaoyan Han;D. He;Yi Zhao;
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是一种有效的抗肿瘤药物，可在多种类型的肿瘤细胞中触发细胞凋亡，而在正常细胞中则不发生。然而，在各种癌症中，不同的机制与TRAIL不敏感有关。TRAIL疗效可通过与增敏剂联合使用而增强。在这项研究中，维诺多尔，一种倍半萜内酯，使弥漫性大B细胞淋巴瘤（DLBCL）细胞对TRAIL诱导的凋亡敏感。维诺多罗增加了死亡受体（DR） 5的表达，用小干扰RNA （siRNA）沉默DR5可降低维诺多罗对TRAIL介导的细胞凋亡的影响。此外，vernodalol上调CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）的表达，这是一种转录因子。用siRNA抑制CHOP降低DR5的表达和维诺多罗诱导的TRAIL治疗增敏。此外，c - Jun N -末端激酶（JNK）抑制剂阻断了vernodalol诱导的DR5上调，表明这种作用依赖于JNK的激活。此外，诱导髓系白血病细胞分化蛋白（Mcl‐1）的下调在维诺多罗/TRAIL诱导的细胞凋亡中发挥了重要作用，因为Mcl‐1的过表达阻止了这种凋亡作用。此外，维诺多罗/TRAIL联合抑制异种移植瘤模型中的肿瘤生长。结果表明，vernodalol通过下调Mcl - 1和上调DR5来增强TRAIL诱导的细胞凋亡，而DR5的作用依赖于JNK的激活和CHOP的诱导。因此，联合TRAIL与维诺多尔（一种天然存在的药物）可能是治疗DLBCL的一种很有希望的方法。
Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a potent anti‐tumor agent that triggers apoptosis in cells from multiple types of carcinoma but not in normal cells. However, diverse mechanisms are associated with insensitivity to TRAIL in various cancers. TRAIL efficacy may be enhanced by combining TRAIL with a sensitizer. In this study, vernodalol, a sesquiterpene lactone, sensitized diffuse large B‐cell lymphoma (DLBCL) cells to TRAIL‐induced apoptosis. Vernodalol increased the expression of death receptor (DR) 5, and silencing of DR5 with a small interfering RNA (siRNA) reduced the effect of vernodalol on TRAIL‐mediated apoptosis. Additionally, vernodalol up‐regulated the expression of CCAAT/enhancer‐binding protein (C/EBP) homologous protein (CHOP), a transcription factor. Inhibition of CHOP with a siRNA diminished DR5 expression and vernodalol‐induced sensitization to the TRAIL treatment. In addition, a c‐Jun N‐terminal kinase (JNK) inhibitor blocked the vernodalol‐induced up‐regulation of DR5, indicating that the effect depended on JNK activation. Furthermore, the down‐regulation of induced myeloid leukaemia cell differentiation protein (Mcl‐1) played an important role in vernodalol/TRAIL‐induced apoptosis, as Mcl‐1 overexpression prevented this apoptotic effect. Moreover, the vernodalol/TRAIL combination inhibited tumor growth in a xenograft model. Based on our results, vernodalol enhanced TRAIL‐induced apoptosis by down‐regulating Mcl‐1 and up‐regulating DR5, and the effects of DR5 depended on JNK activation and CHOP induction. Therefore, combining TRAIL with vernodalol, a naturally occurring agent, may represent a promising therapeutic approach for DLBCL.