Tumor necrosis factor-related apoptosis-inducing ligand is required for tumor necrosis factor alpha-mediated sensitization of human breast cancer cells to chemotherapy.
Tumor necrosis factor-related apoptosis-inducing ligand is required for tumor necrosis factor alpha-mediated sensitization of human breast cancer cells to chemotherapy.
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肿瘤坏死因子相关的凋亡诱导配体是肿瘤坏死因子α介导的人乳腺癌细胞对化疗敏感性所必需的。
DOI：
10.1158/0008-5472.can-06-1633
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发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
Wu,GenSheng
中科院分区：
文献类型：
--
作者：
Xu,Jing;Zhou,Jun-Ying;Wu,GenSheng
肿瘤坏死因子α（tumor necrosis factor α，TNFα）可诱导肿瘤细胞凋亡，使肿瘤细胞对化疗药物敏感，但其致敏机制尚不完全清楚。在这里，我们报道了肿瘤坏死因子α介导的癌细胞对化疗的敏感性涉及TRAIL通路的激活。我们发现，与单独使用任何一种药物相比，TNFα和阿霉素联合治疗乳腺癌细胞显著增加了细胞死亡。联合治疗激活死亡受体和线粒体凋亡途径，而阿霉素单独激活线粒体途径，TNFα未能激活。此外，我们发现TNFα通过转录机制诱导TRAIL。利用报告基因分析结合染色质免疫沉淀分析，我们发现TNFα诱导的TRAIL通过核因子-κB和Sp1结合位点调节。重要的是，通过小干扰RNA沉默下调TRAIL降低了TNFα介导的阿霉素诱导的caspase活化和凋亡，从而增强了乳腺癌细胞对阿霉素的耐药性。总的来说，我们的研究结果表明，TNFα诱导TRAIL是乳腺癌细胞化疗敏感性的关键。（Cancer Res 2006; 66（20）：10092-9）
Tumor necrosis factor α (TNFα) induces apoptosis and sensitizes cancer cells to chemotherapy, but the mechanism underlying its sensitization is not fully understood. Here, we report that TNFα-mediated sensitization of cancer cells to chemotherapy involves activation of the TRAIL pathway. We show that the combined treatment of breast cancer cells with TNFα and Adriamycin significantly increases cell death compared with the treatment with either agent alone. The combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway, and TNFα failed to activate either. Furthermore, we show that TNFα induces TRAIL through a transcriptional mechanism. Using reporter gene assays in conjunction with chromatin immunoprecipitation assays, we show that TRAIL induction by TNFα is regulated via both nuclear factor-κB and Sp1 binding sites. Importantly, down-regulation of TRAIL by small interfering RNA silencing decreased TNFα-mediated Adriamycin-induced caspase activation and apoptosis, and thus enhanced breast cancer cell resistance to Adriamycin. Collectively, our results suggest that induction of TRAIL by TNFα is critical for sensitization of breast cancer cells to chemotherapy. (Cancer Res 2006; 66(20): 10092-9)