Potential mechanism of resistance to TRAIL‐induced apoptosis in Burkitt's lymphoma
Potential mechanism of resistance to TRAIL‐induced apoptosis in Burkitt's lymphoma
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DOI：
10.1111/j.0902-4441.0000.t01-1-ejh2345.x
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发表时间：
2006-01
影响因子：
3.1
通讯作者：
Senji Tafuku;Takehiro Matsuda;Hirochika Kawakami;M. Tomita;H. Yagita;N. Mori
中科院分区：
文献类型：
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作者：
Senji Tafuku;Takehiro Matsuda;Hirochika Kawakami;M. Tomita;H. Yagita;N. Mori
摘要：目的：肿瘤坏死因子家族的成员是敏感细胞中细胞凋亡的强效诱导剂，并且可能适用于旨在通过激活恶性细胞上具有死亡结构域的受体来诱导细胞凋亡的新型抗癌疗法。我们研究了伯基特淋巴瘤（BL）细胞系对肿瘤坏死因子相关凋亡诱导配体（TRAIL）和抗Fas激动剂的敏感性，并研究了BL细胞系对TRAIL和Fas凋亡途径的抗性机制。方法：采用PCR方法检测BL细胞株中EB病毒（EBV）的状态。通过7A 6抗原染色测量暴露于TRAIL和抗Fas激动剂后细胞凋亡的程度。通过流式细胞术和逆转录酶-PCR测定TRAIL受体和Fas的表达。Western印迹分析用于确定促凋亡和抗凋亡蛋白的表达。通过电泳迁移率变动分析评价NF-κB活性。结果：BL细胞对抗Fas激动剂的敏感性依赖于Fas的表达。相反，TRAIL受体的表达与对TRAIL诱导的凋亡的敏感性无关。有趣的是，显示组成性水平NF-κB活化的EBV感染的BL细胞系是TRAIL抗性的。NF-κB抑制剂逆转了对TRAIL诱导的细胞凋亡的抵抗。结论：我们的研究结果表明，EB病毒感染激活NF-κB在BL细胞系对TRAIL诱导的凋亡的抵抗中起重要作用，NF-κB抑制剂可能是临床使用TRAIL治疗BL的有用药物。
Abstract: Objectives: Members of the tumor necrosis factor family are potent inducers of apoptosis in sensitive cells and may be suitable for novel anti‐cancer therapies aimed at inducing apoptosis via the activation of receptors with the death domain on malignant cells. We characterized the sensitivity of Burkitt's lymphoma (BL) cell lines to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and anti‐Fas agonist, and investigated the mechanism of resistance of BL cell lines to TRAIL and Fas apoptotic pathways. Methods: Epstein–Barr virus (EBV) status in BL cell lines was determined by PCR. The extent of apoptosis following exposure to TRAIL and anti‐Fas agonist was measured by 7A6 antigen staining. Expression of TRAIL receptors and Fas was determined by flow cytometry and reverse transcriptase‐PCR. Western blot analyses were used to determine the expression of proapoptotic and antiapoptotic proteins. NF‐κB activity was evaluated by electrophoretic mobility shift assay. Results: The sensitivity of BL cell lines to anti‐Fas agonist depended on the expression of Fas. In contrast, the expression of TRAIL receptors did not correlate with the sensitivity to TRAIL‐induced apoptosis. Interestingly, EBV‐infected BL cell lines which showed constitutive levels of NF‐κB activation, were TRAIL‐resistant. NF‐κB inhibitors reversed the resistance to TRAIL‐induced apoptosis. Conclusions: Our results suggest that activation of NF‐κB by EBV infection plays an important role in resistance of BL cell lines to TRAIL‐induced apoptosis, and that NF‐κB inhibitors may be useful adjuncts in clinical use of TRAIL against BL.