DR5抗体诱导白血病细胞系凋亡与DR5表达
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摘要
背景
肿瘤坏死因子相关的凋亡诱导配体(TNF-related apoptosis inducing ligand, TRAIL)是1995年Wiley等发现的TNF超家族成员,能够诱导多种肿瘤细胞凋亡而对大多数正常细胞无影响。TRAIL通过与肿瘤细胞膜上的相应受体结合诱导细胞凋亡,目前发现TRAIL有5种类型的受体,其中TRAIL受体1(死亡受体4,death receptor 4, DR4)和RAIL受体2(死亡受体5,death receptor 5, DR5)胞内段含有死亡结构域,能够传递凋亡信号,其他三种受体:TRAIL受体3(DcR1)、TRAIL受体4(DcR2)和OPG(Osteoprotegerin)可阻断TRAIL诱导的凋亡,称为“诱骗”受体。虽然天然TRAIL有良好的抗肿瘤作用,但实验发现某些rhTRAIL对正常肝细胞等有细胞毒性,这使人们对其生物安全性产生了怀疑。研究发现一些抗DR4或DR5的功能性单克隆抗体(mAb)能够模拟TRAIL的作用,诱导肿瘤细胞凋亡,且无肝细胞毒性,因此抗人DR4和DR5的功能性单克隆抗体(mAb)成为目前TRAIL肿瘤生物治疗的新靶点。我们利用重组人DR5蛋白免疫BALB/c小鼠,制备了功能性抗DR5单克隆抗体-mDRA-6,前期研究表明mDRA-6可有效诱导多种肿瘤细胞凋亡,同时发现不同肿瘤细胞对其敏感性存有较大差异。虽然肿瘤细胞对mDRA-6敏感性的高低可能与细胞DR5表达、细胞内凋亡信号分子数量及激活状态、细胞内抗凋亡分子变化等诸因素有关,但mDRA-6与细胞DR5结合是启动细胞凋亡的前提,因此推测细胞DR5表达水平是影响mDRA-6诱导细胞凋亡的重要因素。本研究通过分析白血病细胞DR5表达与mDRA-6诱导细胞凋亡的关系,探讨提高细胞DR5表达是增强mDRA-6凋亡诱导作用的有效途径。
目的
检测不同白血病细胞系细胞表面DR5表达、细胞DR5蛋白表达、细胞DR5mRNA表达水平,分析抗人DR5单克隆抗体mDRA-6诱导白血病细胞凋亡与细胞DR5表达的关系。观察维生素E琥珀酸酯(Vitamin E Succinate; VES)对白血病细胞DR5表达的影响,探讨VES增加mDRA-6诱导白血病细胞凋亡作用及可能机制。
方法
MTT法检测mDRA-6对白血病细胞Jurkat、U937、HL-60、Raji和K562细胞的生长抑制作用;Annexin V–FITC/PI双染定量分析白血病细胞凋亡;流式细胞术检测细胞表面DR5表达;免疫印迹技术(Western blotting)检测细胞DR5蛋白表达情况;RT-PCR法检测细胞DR5mRNA表达。
结果
1. MTT检测表明,浓度为10μg /ml的mDRA-6作用12h,白血病Jurkat、U937、HL-60、Raji细胞死亡率分别为88.25%, 61.43%,59.76%,21.98%,K562的细胞死亡率仅为5.23%。5μmol/L、10μmol/L、20μmol/L的VES与mDRA-6分别共同作用于Raji和K562细胞,Raji细胞死亡率分别增加至24.67%(P﹥0.05)、35.65%(P<0.01)和40.22%(P<0.01);K562细胞死亡率增加至6.00%(P﹥0.05)、7.89%(P<0.01)、8.67%(P<0.01)。
2. AnnexinⅤ/PI双染检测5μg/ml的mDRA-6作用白血病细胞12h,Jurkat、U937、HL-60、Raji和K562细胞凋亡率分别为85.96%、50.22%、48.11%、23.40%和7.20%。2μg/ml的mDRA-6单独作用Raji、K562细胞16h,细胞凋亡率分别为20.79%和7.74%,2μg/ml的mDRA-6与10μmol/L的VES共同作用Raji、K562细胞16h,细胞凋亡率分别增至43.18%和16.99%。
3.白血病细胞Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达分别为94.8%、74.71%、58.66%、42.35%和14.92%;Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达与mDRA-6诱导的细胞凋亡呈明显正相关(r=0.9712,t=7.063,p<0.01)。10μmol/L的VES作用Raji、K562细胞12h后,细胞膜DR5表达率分别增加至70.08%和16.38%。
4.免疫印迹技术检测显示,细胞DR5蛋白表达强弱依次为Jurkat、U937、HL-60、Raji和K562。Raji和K562细胞DR5蛋白基础表达量较少,5μmol/L、10μmol/L、20μmol/L的VES分别作用于Raji和K562细胞12h,Raji和K562细胞DR5蛋白表达量均增加,10μmol/L、20μmol/L的VES诱导DR5蛋白表达增加显著。
5.白血病细胞系Jurkat、U937、HL-60、Raji和K562细胞DR5mRNA相对量分别为:306.82±106.36,214.48±93.56,198.47±78.45,123.68±67.23,45.29±26.39;Jurkat、U937、HL-60、Raji和K562细胞DR5mRNA表达与mDRA-6诱导的细胞凋亡呈明显正相关(r=0.9915,t=13.22,p<0.01)。20μmol/L的VES作用Raji细胞12h,细胞DR5mRNA表达显著增加(p<0.05),5μmol/L、10μmol/L的VES作用Raji细胞12h及5μmol/L、10μmol/L、20μmol/L的VES作用K562细胞12h,虽能使细胞DR5 mRNA表达增加,但无统计学意义。
结论
1. mDRA-6能够诱导人白血病Jurkat、U937、HL-60、Raji和K562细胞凋亡,但不同白血病细胞系细胞对mDRA-6的敏感性不同。Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达及DR5mRNA表达与mDRA-6诱导的细胞凋亡呈明显正相关,白血病细胞系细胞对mDRA-6的敏感性不同与细胞DR5表达差异有关。
2. VES增加Raji和K562细胞膜DR5表达、DR5蛋白表达及DR5mRNA表达,同时能够增强mDRA-6对白血病细胞系Raji和K562细胞的凋亡诱导作用。VES增加Raji和K562细胞DR5表达可能是其增强mDRA-6凋亡诱导作用的机制之一。
Background
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily with the ability to induce apoptosis in a wide variety of transformed cell lines of diverse origin. At least five receptors for TRAIL have been identified so far. Two of them, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), sharing a commom intracellular domain, called the death domain (DD), which is indispensable for initiation of the intracellular signaling cascade leading to cell death, are capable of transducing an apoptosis signal, whereas the other three, TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerin (OPG), serve as decoy receptors to block TRAIL-mediated apoptosis. TRAIL has been known to induce apoptosis in a variety of tumor cells and some virally infected cells but not in most normal cells. However, increasing experimental evidences on hrTRAIL-inducing apoptosis of normal cells(especially hepatocytes) were reported in recent studies, arguing against the potential usefulness and safety of soluble TRAIL in cancer therapy. In addition to sTRAIL, monoclonal antibodies (mAbs) against TRAIL-R1 (DR4) or TRAIL-R2 (DR5) with tumoricidal activity are also potential candidates for cancer therapy. There are a number of agonistic mAbs against human DR4 or DR5 reported in previous studies, most of which need crosslinkers to ensure effective killing of tumor cells.
We have cloned the human DR5 gene and prepared the soluble recombinant human DR5 protein (rhDR5), established hybridomas and produced an anti-hDR5 monoclonal antibody, mDRA-6. mDRA-6 showed strong tumoricidal activity in the absence of cross-linking, and had different sensitivity for tumor cells.
Objective
This study is to detect DR5 expression in leukaemia cells, and evaluate the correlation of DR5 expression with apoptosis induced by mDRA-6 in human leukemia cell. The synergistic effect of mDRA-6 and Vitamin E Succinate (VES) on Raji and K562 cells and its possible mechanism were studied.
Methods
Cytotoxic and apoptotic effects of mDRA-6 on Jurkat, U937, HL-60, Raji and K562 cells and the synergistic effect of mDRA-6 and vitamin E succinate (VES) on Raji and K562 cells were detected by MTT and flow cytometry with AnnexinV-FITC/PI staining. DR5 expression on leukaemic cell surface was determined by flow cytometric analysis of the binding of anti-DR5 mAb; DR5 total protein expression in leukaemic cells were detected by western blot. The RT-PCR(semi-quantitative reverse transcription polymerase chain reaction)method was used to detect the DR5 mRNA expression in leukaemic cells.
Results
①The specific cytotoxicity of the mDRA-6 against Jurkat cells was 88.25%, U937 cells was 61.43%,HL-60 cells was 59.76%, Raji cells was 21.98%, and K562 cells was 5.23% respectively at the concentration of 10mg/L for 12 hours by MTT analysis. The combination of mDRA-6 and VES exhibited synergistic effect on Raji cells and K562 cells. 10μg/mL of mDRA-6 and 20μmol/L of VES killed 40.22% Raji cells and 8.67% K562 cells.
②The apoptotic rate of the Jurkat, U937, HL-60, Raji and K562 cells was 50.22%, 48.11%, 23.40% and 7.20%, respectively ,in the presence 5mg/L mDRA-6 for 12 hours determined by flow cytometry with Annexin V-FITC/PI staining. The apoptotic rate of Raji and K562 celsl was increased to 43.18% and 16.99% respectively, after treated with 2μg/mL of mDRA-6 and 10μmol/L of VES for 16 hours.
③The DR5 expression level on leukaemia cell surface were 94.8% for Jurkat cells, 74.71% for U937 cells, 58.66% for HL-60 cells ,42.35%for Raji cells and 14.92% for K562 cells respectively. The DR5 expression level of Raji cells and K562 cells treated with 10μmol/L of VES for 12 hours increased to 70.08% and 16.38% respectively.
④Western blotting revealed that expression levels of the DR5 protein in Jurkat, U937, HL-60, Raji and K562 cells were unequal.The DR5 protein expression levels in Raji cells and K562 cells were lower. However, the DR5 protein levels of Raji cells and K562 cells treated with VES increased .⑤The mRNA expression of DR5 in Jurkat,U937, HL-60, Raji and K562 cells were analyzed by RT-PCR. The mRNA expression of DR5 in Raji cells treated with 20μmol/L of VES for 12 hours increased (P<0.05) obviously.
Conclusion
①The expression level of DR5 in Jurkat, U937, HL-60, Raji and K562 cells were different. There is the correlation between DR5 expression and human leukemia apoptotic rate induced by mDRA-6 in human leukaemia cell.
②Combination of mDRA-6 and vitamin E succinate has synergistic effect of apoptosis on Raji and K562 cells by increasing DR5 expression on Raji, K562 cells treated with vitamin E succinate.
肿瘤坏死因子相关的凋亡诱导配体(TNF-related apoptosis inducing ligand, TRAIL)是1995年Wiley等发现的TNF超家族成员,能够诱导多种肿瘤细胞凋亡而对大多数正常细胞无影响。TRAIL通过与肿瘤细胞膜上的相应受体结合诱导细胞凋亡,目前发现TRAIL有5种类型的受体,其中TRAIL受体1(死亡受体4,death receptor 4, DR4)和RAIL受体2(死亡受体5,death receptor 5, DR5)胞内段含有死亡结构域,能够传递凋亡信号,其他三种受体:TRAIL受体3(DcR1)、TRAIL受体4(DcR2)和OPG(Osteoprotegerin)可阻断TRAIL诱导的凋亡,称为“诱骗”受体。虽然天然TRAIL有良好的抗肿瘤作用,但实验发现某些rhTRAIL对正常肝细胞等有细胞毒性,这使人们对其生物安全性产生了怀疑。研究发现一些抗DR4或DR5的功能性单克隆抗体(mAb)能够模拟TRAIL的作用,诱导肿瘤细胞凋亡,且无肝细胞毒性,因此抗人DR4和DR5的功能性单克隆抗体(mAb)成为目前TRAIL肿瘤生物治疗的新靶点。我们利用重组人DR5蛋白免疫BALB/c小鼠,制备了功能性抗DR5单克隆抗体-mDRA-6,前期研究表明mDRA-6可有效诱导多种肿瘤细胞凋亡,同时发现不同肿瘤细胞对其敏感性存有较大差异。虽然肿瘤细胞对mDRA-6敏感性的高低可能与细胞DR5表达、细胞内凋亡信号分子数量及激活状态、细胞内抗凋亡分子变化等诸因素有关,但mDRA-6与细胞DR5结合是启动细胞凋亡的前提,因此推测细胞DR5表达水平是影响mDRA-6诱导细胞凋亡的重要因素。本研究通过分析白血病细胞DR5表达与mDRA-6诱导细胞凋亡的关系,探讨提高细胞DR5表达是增强mDRA-6凋亡诱导作用的有效途径。
目的
检测不同白血病细胞系细胞表面DR5表达、细胞DR5蛋白表达、细胞DR5mRNA表达水平,分析抗人DR5单克隆抗体mDRA-6诱导白血病细胞凋亡与细胞DR5表达的关系。观察维生素E琥珀酸酯(Vitamin E Succinate; VES)对白血病细胞DR5表达的影响,探讨VES增加mDRA-6诱导白血病细胞凋亡作用及可能机制。
方法
MTT法检测mDRA-6对白血病细胞Jurkat、U937、HL-60、Raji和K562细胞的生长抑制作用;Annexin V–FITC/PI双染定量分析白血病细胞凋亡;流式细胞术检测细胞表面DR5表达;免疫印迹技术(Western blotting)检测细胞DR5蛋白表达情况;RT-PCR法检测细胞DR5mRNA表达。
结果
1. MTT检测表明,浓度为10μg /ml的mDRA-6作用12h,白血病Jurkat、U937、HL-60、Raji细胞死亡率分别为88.25%, 61.43%,59.76%,21.98%,K562的细胞死亡率仅为5.23%。5μmol/L、10μmol/L、20μmol/L的VES与mDRA-6分别共同作用于Raji和K562细胞,Raji细胞死亡率分别增加至24.67%(P﹥0.05)、35.65%(P<0.01)和40.22%(P<0.01);K562细胞死亡率增加至6.00%(P﹥0.05)、7.89%(P<0.01)、8.67%(P<0.01)。
2. AnnexinⅤ/PI双染检测5μg/ml的mDRA-6作用白血病细胞12h,Jurkat、U937、HL-60、Raji和K562细胞凋亡率分别为85.96%、50.22%、48.11%、23.40%和7.20%。2μg/ml的mDRA-6单独作用Raji、K562细胞16h,细胞凋亡率分别为20.79%和7.74%,2μg/ml的mDRA-6与10μmol/L的VES共同作用Raji、K562细胞16h,细胞凋亡率分别增至43.18%和16.99%。
3.白血病细胞Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达分别为94.8%、74.71%、58.66%、42.35%和14.92%;Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达与mDRA-6诱导的细胞凋亡呈明显正相关(r=0.9712,t=7.063,p<0.01)。10μmol/L的VES作用Raji、K562细胞12h后,细胞膜DR5表达率分别增加至70.08%和16.38%。
4.免疫印迹技术检测显示,细胞DR5蛋白表达强弱依次为Jurkat、U937、HL-60、Raji和K562。Raji和K562细胞DR5蛋白基础表达量较少,5μmol/L、10μmol/L、20μmol/L的VES分别作用于Raji和K562细胞12h,Raji和K562细胞DR5蛋白表达量均增加,10μmol/L、20μmol/L的VES诱导DR5蛋白表达增加显著。
5.白血病细胞系Jurkat、U937、HL-60、Raji和K562细胞DR5mRNA相对量分别为:306.82±106.36,214.48±93.56,198.47±78.45,123.68±67.23,45.29±26.39;Jurkat、U937、HL-60、Raji和K562细胞DR5mRNA表达与mDRA-6诱导的细胞凋亡呈明显正相关(r=0.9915,t=13.22,p<0.01)。20μmol/L的VES作用Raji细胞12h,细胞DR5mRNA表达显著增加(p<0.05),5μmol/L、10μmol/L的VES作用Raji细胞12h及5μmol/L、10μmol/L、20μmol/L的VES作用K562细胞12h,虽能使细胞DR5 mRNA表达增加,但无统计学意义。
结论
1. mDRA-6能够诱导人白血病Jurkat、U937、HL-60、Raji和K562细胞凋亡,但不同白血病细胞系细胞对mDRA-6的敏感性不同。Jurkat、U937、HL-60、Raji和K562细胞表面DR5表达及DR5mRNA表达与mDRA-6诱导的细胞凋亡呈明显正相关,白血病细胞系细胞对mDRA-6的敏感性不同与细胞DR5表达差异有关。
2. VES增加Raji和K562细胞膜DR5表达、DR5蛋白表达及DR5mRNA表达,同时能够增强mDRA-6对白血病细胞系Raji和K562细胞的凋亡诱导作用。VES增加Raji和K562细胞DR5表达可能是其增强mDRA-6凋亡诱导作用的机制之一。
Background
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily with the ability to induce apoptosis in a wide variety of transformed cell lines of diverse origin. At least five receptors for TRAIL have been identified so far. Two of them, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), sharing a commom intracellular domain, called the death domain (DD), which is indispensable for initiation of the intracellular signaling cascade leading to cell death, are capable of transducing an apoptosis signal, whereas the other three, TRAIL-R3 (DcR1), TRAIL-R4 (DcR2) and osteoprotegerin (OPG), serve as decoy receptors to block TRAIL-mediated apoptosis. TRAIL has been known to induce apoptosis in a variety of tumor cells and some virally infected cells but not in most normal cells. However, increasing experimental evidences on hrTRAIL-inducing apoptosis of normal cells(especially hepatocytes) were reported in recent studies, arguing against the potential usefulness and safety of soluble TRAIL in cancer therapy. In addition to sTRAIL, monoclonal antibodies (mAbs) against TRAIL-R1 (DR4) or TRAIL-R2 (DR5) with tumoricidal activity are also potential candidates for cancer therapy. There are a number of agonistic mAbs against human DR4 or DR5 reported in previous studies, most of which need crosslinkers to ensure effective killing of tumor cells.
We have cloned the human DR5 gene and prepared the soluble recombinant human DR5 protein (rhDR5), established hybridomas and produced an anti-hDR5 monoclonal antibody, mDRA-6. mDRA-6 showed strong tumoricidal activity in the absence of cross-linking, and had different sensitivity for tumor cells.
Objective
This study is to detect DR5 expression in leukaemia cells, and evaluate the correlation of DR5 expression with apoptosis induced by mDRA-6 in human leukemia cell. The synergistic effect of mDRA-6 and Vitamin E Succinate (VES) on Raji and K562 cells and its possible mechanism were studied.
Methods
Cytotoxic and apoptotic effects of mDRA-6 on Jurkat, U937, HL-60, Raji and K562 cells and the synergistic effect of mDRA-6 and vitamin E succinate (VES) on Raji and K562 cells were detected by MTT and flow cytometry with AnnexinV-FITC/PI staining. DR5 expression on leukaemic cell surface was determined by flow cytometric analysis of the binding of anti-DR5 mAb; DR5 total protein expression in leukaemic cells were detected by western blot. The RT-PCR(semi-quantitative reverse transcription polymerase chain reaction)method was used to detect the DR5 mRNA expression in leukaemic cells.
Results
①The specific cytotoxicity of the mDRA-6 against Jurkat cells was 88.25%, U937 cells was 61.43%,HL-60 cells was 59.76%, Raji cells was 21.98%, and K562 cells was 5.23% respectively at the concentration of 10mg/L for 12 hours by MTT analysis. The combination of mDRA-6 and VES exhibited synergistic effect on Raji cells and K562 cells. 10μg/mL of mDRA-6 and 20μmol/L of VES killed 40.22% Raji cells and 8.67% K562 cells.
②The apoptotic rate of the Jurkat, U937, HL-60, Raji and K562 cells was 50.22%, 48.11%, 23.40% and 7.20%, respectively ,in the presence 5mg/L mDRA-6 for 12 hours determined by flow cytometry with Annexin V-FITC/PI staining. The apoptotic rate of Raji and K562 celsl was increased to 43.18% and 16.99% respectively, after treated with 2μg/mL of mDRA-6 and 10μmol/L of VES for 16 hours.
③The DR5 expression level on leukaemia cell surface were 94.8% for Jurkat cells, 74.71% for U937 cells, 58.66% for HL-60 cells ,42.35%for Raji cells and 14.92% for K562 cells respectively. The DR5 expression level of Raji cells and K562 cells treated with 10μmol/L of VES for 12 hours increased to 70.08% and 16.38% respectively.
④Western blotting revealed that expression levels of the DR5 protein in Jurkat, U937, HL-60, Raji and K562 cells were unequal.The DR5 protein expression levels in Raji cells and K562 cells were lower. However, the DR5 protein levels of Raji cells and K562 cells treated with VES increased .⑤The mRNA expression of DR5 in Jurkat,U937, HL-60, Raji and K562 cells were analyzed by RT-PCR. The mRNA expression of DR5 in Raji cells treated with 20μmol/L of VES for 12 hours increased (P<0.05) obviously.
Conclusion
①The expression level of DR5 in Jurkat, U937, HL-60, Raji and K562 cells were different. There is the correlation between DR5 expression and human leukemia apoptotic rate induced by mDRA-6 in human leukaemia cell.
②Combination of mDRA-6 and vitamin E succinate has synergistic effect of apoptosis on Raji and K562 cells by increasing DR5 expression on Raji, K562 cells treated with vitamin E succinate.
引文
1 Wiley SR,Schrooley K,Smolak PJ,et al. Identification and chraracterization of a new member of the TNF family that induces apoptosis. Immunity, 1995, 3(6): 673–682.
2 Mérino D, Lalaoui N, Morizot A, et al. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2 [J]. Mol Cell Biol, 2006, 16: 7046?7055.
3 Chen S, Liu X, Yue P, et al. CCAAT/enhancer binding protein homologous protein-dependent death receptor 5 induction and ubiquitin/proteasome-mediated cellular FLICE-inhibitory protein down-regulation contribute to enhancement of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by dimethyl-celecoxib in human non-small-cell lung cancer cells [J]. Mol Pharmacol, 2007, 72: 1269?1279.
4 Schneider,P ,T home,M ,B urns,K ,B odmer,J. L ,H ofmann,K ,K ataoka,T ,Holler, N,Tschopp, J. TRAIL receptors 1 (DR4) and 2(DR5) signal FADD-dependent apoptosis and activate NF-kappaB.(1997)Im munity7 ,831-836
5 Muhlenbeck, F, Haas, E, Schwenzer, R, SchubeM G, Grell, M,Smith, C,Scheurich, P, and Wajant, H. TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK)via caspase-dependent and caspase-independent pathways.(1998) J. Biol. Chem 273, 33091-33098
6 Jeremias, I, Debatin, K. M. TRAIL induces apoptosis and activation of NF-kappaB. (1998).Eur CytokineNet,9,687-688
7 Sheikh MS,Fornace AJ,Jr.Death and decoy receptors and P53-mediated apoptosis. Leukemia,2000;14:1509.
8 Kruyt F. TRAIL and cancer therapy. Cancer Lett, 2008, 263: 14-25
9 Chuntharapai A, Dodge K, Grimmer K ,et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol. 2001 ,166(8): 4891～4898.
10 Ichikawa K, Liu W, Zhao L , et al . Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity . Nat Med , 2001 , 7 (8) : 954～960.
11 Truneh A, Sharma S, Silverman C, et al.Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor. J Biol Chem, 2000 ,275(30):23319-23325.
12 Shigeno M, Nakao K, Ichikawa T et al .Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-KappaB inactivation .Oncogene, 2003; 22: 1653～1662
13 LaVallee T M, Zhan X H, Johnson M S et al .2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway .Cancer Res, 2003;63:468～475
14 Wen J H, Ramadevi N, Nguyen D et al . Antileukemic durgs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute lecukemia cells. Blood ,2000;96(12): 3900～3906
15 Koornstra JJ, Kleibeuker JH, van Geelen CM, et al. Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas [J]. J Pathol, 2003, 200: 327-335.
16 McCarthy MM, Sznol M, DiVito KA, et al. Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer [J]. Clin Cancer Res, 2005, 11: 5188?5194.
17 Takeda K, Yamaguchi N, Akiba H, et al. Induction of tumorspecific T cell immunity by anti-DR5 antibody therapy [J]. J Exp Med, 2004, 199: 437?448.
18 Uno T, Takeda K, Kojima Y, et al. Eradication of established tumors in mice by a combination antibody-based therapy [J]. Nat Med, 2006, 12: 693?698.
19 Crispen PL, Uzzo RG, Golovine K, et al. Vitamin E succinate inhibits NFkappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention[J].Prostate,2007,67(6):582-590.
20 Tomasetti M, Rippo MR, Alleva R, etal. Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells [J].Br J Cancer,2004,90(8):1644-1653.
21 Stapelberg M, Tomasetti M, Alleva R, et al. alpha-Tocopheryl succinate inhibits proliferation of mesothelioma cells by selective down-regulation of fibroblast growth factor receptors[J].Biochem Biophys Res Commun, 2004,318(3):636-641.
22赵缇,王红祥,毛红,等.肿瘤坏死因子相关凋亡诱导配体TRAIL及其受体在急性髓系白血病细胞中的表达及意义中国实验血液学杂志,2005,13(1):65～69.
23 Gong B, Almasan A. Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells.CancerRes,2000,60(20):5754～5760.
24 Gu X,Song X,Dong Y,et al.Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo[J].Clin Cancer Res,2008,14(6):1840-1848.
25 Gu X, Schwartz JL, Pang X, et al. Cytotoxicity of liposomal alphatocopheryl succinate towards hamster cheek pouch carcinoma(HCPC-1)cells in culture [J].Cancer Lett,2006,239(2):281-291.
26 Stapelberg M, Gellert N, Swettenham E,et al. Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrineloop: mechanism and the role of oxidative stress [J]. J Biol Chem, 2005,280(27):25369-25376.
27张海金,吴坤TRAIL途径在维生素E琥珀酸酯诱导人胃癌细胞凋亡中的作用癌变畸变突变2009,21(1):21-23
28 Zeng Y,Wu XX,Fiscella M,et al. Monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) induces apoptosis in primary renal cell carcinoma cells in vitro and inhibits tumor growth in vivo[J].Int J Oncol,2006,28(2):421-30.
1 Krammer PH , CD95′s deadly mission in the immune system. Nature 2000,407(6805): 789～795
2 Hou Q. Effect of staurosporine induced apoptosis of MCF7/GFP-Bax stable cell line on Bax translocation from cytosolinto mitochondria [J]. Acta Pharm Sin, 2008, 43: 378-382.
3 Wiley S R ,Schoole Y K,Smolak P J,et al. Identification and characterization of a new member of the TNF family that induces apoptosis [J]. Immunity, 1995, 3:673～682.
4 Pag G ,O Rourke K,Chinnaiyan A M, et al.The receptor for the cytotoxic ligand TRAIL [J] . Science,1997,276(5309):111～113.
5 Chen S, Liu X, Yue P, et al. CCAAT/enhancer binding protein homologous protein-dependent death receptor 5 induction and ubiquitin/proteasome-mediated cellular FLICE-inhibitory protein down-regulation contribute to enhancement of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by dimethyl-celecoxib in human non-small-cell lung cancer cells [J]. Mol Pharmacol, 2007, 72: 1269-1279.
6 Pan G, Ni J,Wei Y F,et al.An antagonist decoy receptor and adeathdomain-containing receptor for TRAIL [J]. Science,1997,277(5327):815～818.
7 Bouralexis S, Findlay DM, Evdokiou A. Death to the bad guys: targeting cancer via Apo2L/TRAIL [J]. Apoptosis, 2005, 10: 35-51.
8 Pan G, Ni J,Wei Y F,et al.An antagonist decoy receptor and adeath domain-containing receptor for TRAIL [J]. Science,1997,277(5327):815～818.
9 Mariathasan S, Newton K, Monack D M, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf [J]. Nature, 2004, 430(6996): 213～218.
10 Chinnaiyan A M, O .Rourke K,Yu G L,et al.Signal transduction by DR3,a death domain-containing receptor related to TNFR-1 and CD95 [J]. Science, 1996, 274(5289): 990～992.
11 Yan M,Wang L C, Hymowitz S G, et al.Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors[J]. Science, 2000, 290(5491): 523～527.
12 Bouralexis S, Findlay DM, Atkins GJ, et al. Progressiveresistance of BTK-143 osteosarcoma cells to Apo2L/TRAILinduced apoptosis is mediated by acquisition of DcR2/TRAILR4expression: resensitisation with chemotherapy [J]. Br JCancer, 2003, 89: 206-214.
13 Liang G P,Yang S M, Luo X D.The research progress of trail receptors and their signal transduction[J]. Foreign Med Sci (Clin Biochem Lab Med Fioreign Med Sci) (国外医学.临床生物化学与检验学分册),2001,22(3):119～120.
14 El-Deiry WS.Insights into cancer therapeutic designbased on p53 and TRAIL receptor signaling [J].Cell Death Differ,2001,8(11):1066 - 75.
15 Wajant H, Pfizenmaier K, Scheurich P . TNF-related apoptosis inducing ligang(TRAIL) and its receptors in tumor surveillance and cancer therapy. Apoptosis,2002,7(5): 449～459.
16 Ashkenazi A and Dixit VM. Deat h receptors : signaling and modulation[J] . Science , 1998,281:1305-1308.
17 MacFarlane M ,Ahmad M,Srinivasula SM,et al.Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL[J].J Biol Chem,1997,272: 25417-25420.
18 Pan G, Ni J , Yu G, and Wei YF. TRUNDD , a new member of t he TRAIL receptor family that antagonizes TRAIL signalling[J ].FEBS Lett,1998,424:41-45.
19 Wu XX ,Ogawa O,and Kakehi Y.TRAIL and chemotherapeutic drugs in cancer therapy [J].Vitam Horm,2004,67:365-383.
20 Berger T, Kretzler M. TRAIL-induced apoptosis is independentof the mitochondrial apoptosis mediator DAP3. Biochem Biophys Res Commun 2002; 297: 880-884.
21 Daniel P T, Wieder T, Sturm I, et al. The kiss of death:promises and failures of death receptor ligands in cancer therapy[J].Leukemia,2001,15:1022～32
22 Luo X , Budihardjo I , Zou H , et al . Bid , a Bcl2 interacting protein , mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors[J].Cell,1998,94:481-490.
23 Krueger A, Baumann S, Krammer PH, et al. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol.2001;21: 8247-8254.
24 MacFarlane M ,Harper N ,Snowden RT ,et al . Mechanisms of resistance to TRAIL induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene , 2002 ,21 (44) :6809 - 6818.
25 Zhang XD,Franco A,Myers K,et al .Relation of TNF-related apoptosis-inducing ligand(TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma .Cancer rsearch,1999.59:2747～2753.
26 Munshi A, Pappas G, Honda T, et al.TRAIL(APO-2L) induces apoptosis in humanprostate cancer cells that is inhibitable by Bcl-2.Oncogene.2001;20:3757-3765.
27 Gilbertson S et al. Transformation, translation and TRAIL: anunexpected intersection. Cytokine Growth Factor Rev, 2008, 19: 167-172
28 Munshi A, Pappas G, Honda T, et al.TRAIL(APO-2L) induces apoptosis in human prostate cancer cells that is inhibitable by Bcl-2.Oncogene.2001;20:3757-3765.
29 Burns TF, El-Deiry WS. Identification of inhibitors of TRAILinduced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem. 2001; 276: 37879-37886.
30 Fulda S, Meyer E, Debatin KM. Inhibition of TRAIL-induced apoptosis by bcl-2 overexpression. Oncogene.2002;21: 2283-2294.
31 Petrella A et al. Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. Eur J Cancer, 2006, 42: 3287-3293
32 DengY, LinY,Wu X. TRAIL-induced apoptosis requires Baxdependent mitochondrial release of Smac/DIABLO. Genes Dev.2002;16(1):33-45.
33 Ehrhardt H, Fulda S, Schmed I, et al. TRAIL induced survival and proliferation in cancer cells resistant toward TRAIL-induced apoptosis mediated by NF-kappaB[J]. Oncogene, 2003,22:3842～52
34 Shetty S,Gladden J B, Henson E S, et al.Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) up regulations death receptor5 (DR5) mediated by NF-kappaB activation in epithelial derved cell lines. Apoptosis, 2002,7(5):413～20
35 Hu Z,Tao YG,Tang FQ,et al.Effect of JIP on the proliferation and apoptosis of nasopharyngeal carcinoma cells through interaction with JNK mediated pathway[J]. Prog Biochem Biophys,2003,30(4) :579-585.
36 Chen X, Kandasamy K, Srivastava R K. Differential roles of RelA(p65) and c-Rel subunits of nuclear factor kappaB in tumor necrosis factor-relatedapoptosis-inducing ligand signaling.Cancer Res,2003,63(5):1059～66
37 Baetu TM, Kwon H, Sharma S, Grandvaux N, Hiscott J. Disruption of NF-kappaB signaling reveals a novel role for NfkappaB in the regulation of TNF-related apoptosis-inducing ligand expression. J Immunol 2001; 167: 3164-3173.
38 Koschny R, Walczak H, Ganten T. The promise of TRAILpotential and risks of a novel anticancer therapy [J]. J Mol Med, 2007, 85: 923-935.
39 Cretney E, Takeda K, Smyth MJ. Cancer: novel therapeutic strategies that exploit the TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway [J]. Int J Biochem Cell Biol, 2007, 39: 280-286.
40 Ganten TM,Koschny R,Sykora J,et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs [J]. Clin Cancer Res,2006,12:2640-1246
41 Guan B, Yue P, Clayman GL, et al. Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene [J]. J Cell Physiol, 2001, 188: 98-105.
42 Seol JW, Chaudhari AA, Lee YJ, et al. Regulation of DR-5 protein and mitochondrial transmembrane potential by gemcitabine, a possible mechanism of gemcitabine-enhanced TRAIL-induced apoptosis [J]. Oncol Rep, 2007, 18: 523-529.
43 Nagane M, Pan G, Weddle JJ, et al. Increased death receptor 5 expression by chemotherapeutic agents in human gliomascauses synergistic cytotoxicity with tumor necrosis factorrelated apoptosis-inducing ligand in vitro and in vivo [J]. Cancer Res, 2000, 60: 847-853.
44 Takeda K, Yamaguchi N, Akiba H, et al. Induction of tumorspecific T cell immunity by anti-DR5 antibody therapy [J]. J Exp Med, 2004, 199: 437-448.
2 Mérino D, Lalaoui N, Morizot A, et al. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2 [J]. Mol Cell Biol, 2006, 16: 7046?7055.
3 Chen S, Liu X, Yue P, et al. CCAAT/enhancer binding protein homologous protein-dependent death receptor 5 induction and ubiquitin/proteasome-mediated cellular FLICE-inhibitory protein down-regulation contribute to enhancement of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by dimethyl-celecoxib in human non-small-cell lung cancer cells [J]. Mol Pharmacol, 2007, 72: 1269?1279.
4 Schneider,P ,T home,M ,B urns,K ,B odmer,J. L ,H ofmann,K ,K ataoka,T ,Holler, N,Tschopp, J. TRAIL receptors 1 (DR4) and 2(DR5) signal FADD-dependent apoptosis and activate NF-kappaB.(1997)Im munity7 ,831-836
5 Muhlenbeck, F, Haas, E, Schwenzer, R, SchubeM G, Grell, M,Smith, C,Scheurich, P, and Wajant, H. TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK)via caspase-dependent and caspase-independent pathways.(1998) J. Biol. Chem 273, 33091-33098
6 Jeremias, I, Debatin, K. M. TRAIL induces apoptosis and activation of NF-kappaB. (1998).Eur CytokineNet,9,687-688
7 Sheikh MS,Fornace AJ,Jr.Death and decoy receptors and P53-mediated apoptosis. Leukemia,2000;14:1509.
8 Kruyt F. TRAIL and cancer therapy. Cancer Lett, 2008, 263: 14-25
9 Chuntharapai A, Dodge K, Grimmer K ,et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol. 2001 ,166(8): 4891～4898.
10 Ichikawa K, Liu W, Zhao L , et al . Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity . Nat Med , 2001 , 7 (8) : 954～960.
11 Truneh A, Sharma S, Silverman C, et al.Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor. J Biol Chem, 2000 ,275(30):23319-23325.
12 Shigeno M, Nakao K, Ichikawa T et al .Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-KappaB inactivation .Oncogene, 2003; 22: 1653～1662
13 LaVallee T M, Zhan X H, Johnson M S et al .2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway .Cancer Res, 2003;63:468～475
14 Wen J H, Ramadevi N, Nguyen D et al . Antileukemic durgs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute lecukemia cells. Blood ,2000;96(12): 3900～3906
15 Koornstra JJ, Kleibeuker JH, van Geelen CM, et al. Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas [J]. J Pathol, 2003, 200: 327-335.
16 McCarthy MM, Sznol M, DiVito KA, et al. Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer [J]. Clin Cancer Res, 2005, 11: 5188?5194.
17 Takeda K, Yamaguchi N, Akiba H, et al. Induction of tumorspecific T cell immunity by anti-DR5 antibody therapy [J]. J Exp Med, 2004, 199: 437?448.
18 Uno T, Takeda K, Kojima Y, et al. Eradication of established tumors in mice by a combination antibody-based therapy [J]. Nat Med, 2006, 12: 693?698.
19 Crispen PL, Uzzo RG, Golovine K, et al. Vitamin E succinate inhibits NFkappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention[J].Prostate,2007,67(6):582-590.
20 Tomasetti M, Rippo MR, Alleva R, etal. Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells [J].Br J Cancer,2004,90(8):1644-1653.
21 Stapelberg M, Tomasetti M, Alleva R, et al. alpha-Tocopheryl succinate inhibits proliferation of mesothelioma cells by selective down-regulation of fibroblast growth factor receptors[J].Biochem Biophys Res Commun, 2004,318(3):636-641.
22赵缇,王红祥,毛红,等.肿瘤坏死因子相关凋亡诱导配体TRAIL及其受体在急性髓系白血病细胞中的表达及意义中国实验血液学杂志,2005,13(1):65～69.
23 Gong B, Almasan A. Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells.CancerRes,2000,60(20):5754～5760.
24 Gu X,Song X,Dong Y,et al.Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo[J].Clin Cancer Res,2008,14(6):1840-1848.
25 Gu X, Schwartz JL, Pang X, et al. Cytotoxicity of liposomal alphatocopheryl succinate towards hamster cheek pouch carcinoma(HCPC-1)cells in culture [J].Cancer Lett,2006,239(2):281-291.
26 Stapelberg M, Gellert N, Swettenham E,et al. Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrineloop: mechanism and the role of oxidative stress [J]. J Biol Chem, 2005,280(27):25369-25376.
27张海金,吴坤TRAIL途径在维生素E琥珀酸酯诱导人胃癌细胞凋亡中的作用癌变畸变突变2009,21(1):21-23
28 Zeng Y,Wu XX,Fiscella M,et al. Monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) induces apoptosis in primary renal cell carcinoma cells in vitro and inhibits tumor growth in vivo[J].Int J Oncol,2006,28(2):421-30.
1 Krammer PH , CD95′s deadly mission in the immune system. Nature 2000,407(6805): 789～795
2 Hou Q. Effect of staurosporine induced apoptosis of MCF7/GFP-Bax stable cell line on Bax translocation from cytosolinto mitochondria [J]. Acta Pharm Sin, 2008, 43: 378-382.
3 Wiley S R ,Schoole Y K,Smolak P J,et al. Identification and characterization of a new member of the TNF family that induces apoptosis [J]. Immunity, 1995, 3:673～682.
4 Pag G ,O Rourke K,Chinnaiyan A M, et al.The receptor for the cytotoxic ligand TRAIL [J] . Science,1997,276(5309):111～113.
5 Chen S, Liu X, Yue P, et al. CCAAT/enhancer binding protein homologous protein-dependent death receptor 5 induction and ubiquitin/proteasome-mediated cellular FLICE-inhibitory protein down-regulation contribute to enhancement of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by dimethyl-celecoxib in human non-small-cell lung cancer cells [J]. Mol Pharmacol, 2007, 72: 1269-1279.
6 Pan G, Ni J,Wei Y F,et al.An antagonist decoy receptor and adeathdomain-containing receptor for TRAIL [J]. Science,1997,277(5327):815～818.
7 Bouralexis S, Findlay DM, Evdokiou A. Death to the bad guys: targeting cancer via Apo2L/TRAIL [J]. Apoptosis, 2005, 10: 35-51.
8 Pan G, Ni J,Wei Y F,et al.An antagonist decoy receptor and adeath domain-containing receptor for TRAIL [J]. Science,1997,277(5327):815～818.
9 Mariathasan S, Newton K, Monack D M, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf [J]. Nature, 2004, 430(6996): 213～218.
10 Chinnaiyan A M, O .Rourke K,Yu G L,et al.Signal transduction by DR3,a death domain-containing receptor related to TNFR-1 and CD95 [J]. Science, 1996, 274(5289): 990～992.
11 Yan M,Wang L C, Hymowitz S G, et al.Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors[J]. Science, 2000, 290(5491): 523～527.
12 Bouralexis S, Findlay DM, Atkins GJ, et al. Progressiveresistance of BTK-143 osteosarcoma cells to Apo2L/TRAILinduced apoptosis is mediated by acquisition of DcR2/TRAILR4expression: resensitisation with chemotherapy [J]. Br JCancer, 2003, 89: 206-214.
13 Liang G P,Yang S M, Luo X D.The research progress of trail receptors and their signal transduction[J]. Foreign Med Sci (Clin Biochem Lab Med Fioreign Med Sci) (国外医学.临床生物化学与检验学分册),2001,22(3):119～120.
14 El-Deiry WS.Insights into cancer therapeutic designbased on p53 and TRAIL receptor signaling [J].Cell Death Differ,2001,8(11):1066 - 75.
15 Wajant H, Pfizenmaier K, Scheurich P . TNF-related apoptosis inducing ligang(TRAIL) and its receptors in tumor surveillance and cancer therapy. Apoptosis,2002,7(5): 449～459.
16 Ashkenazi A and Dixit VM. Deat h receptors : signaling and modulation[J] . Science , 1998,281:1305-1308.
17 MacFarlane M ,Ahmad M,Srinivasula SM,et al.Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL[J].J Biol Chem,1997,272: 25417-25420.
18 Pan G, Ni J , Yu G, and Wei YF. TRUNDD , a new member of t he TRAIL receptor family that antagonizes TRAIL signalling[J ].FEBS Lett,1998,424:41-45.
19 Wu XX ,Ogawa O,and Kakehi Y.TRAIL and chemotherapeutic drugs in cancer therapy [J].Vitam Horm,2004,67:365-383.
20 Berger T, Kretzler M. TRAIL-induced apoptosis is independentof the mitochondrial apoptosis mediator DAP3. Biochem Biophys Res Commun 2002; 297: 880-884.
21 Daniel P T, Wieder T, Sturm I, et al. The kiss of death:promises and failures of death receptor ligands in cancer therapy[J].Leukemia,2001,15:1022～32
22 Luo X , Budihardjo I , Zou H , et al . Bid , a Bcl2 interacting protein , mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors[J].Cell,1998,94:481-490.
23 Krueger A, Baumann S, Krammer PH, et al. FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol.2001;21: 8247-8254.
24 MacFarlane M ,Harper N ,Snowden RT ,et al . Mechanisms of resistance to TRAIL induced apoptosis in primary B cell chronic lymphocytic leukaemia. Oncogene , 2002 ,21 (44) :6809 - 6818.
25 Zhang XD,Franco A,Myers K,et al .Relation of TNF-related apoptosis-inducing ligand(TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma .Cancer rsearch,1999.59:2747～2753.
26 Munshi A, Pappas G, Honda T, et al.TRAIL(APO-2L) induces apoptosis in humanprostate cancer cells that is inhibitable by Bcl-2.Oncogene.2001;20:3757-3765.
27 Gilbertson S et al. Transformation, translation and TRAIL: anunexpected intersection. Cytokine Growth Factor Rev, 2008, 19: 167-172
28 Munshi A, Pappas G, Honda T, et al.TRAIL(APO-2L) induces apoptosis in human prostate cancer cells that is inhibitable by Bcl-2.Oncogene.2001;20:3757-3765.
29 Burns TF, El-Deiry WS. Identification of inhibitors of TRAILinduced death (ITIDs) in the TRAIL-sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem. 2001; 276: 37879-37886.
30 Fulda S, Meyer E, Debatin KM. Inhibition of TRAIL-induced apoptosis by bcl-2 overexpression. Oncogene.2002;21: 2283-2294.
31 Petrella A et al. Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. Eur J Cancer, 2006, 42: 3287-3293
32 DengY, LinY,Wu X. TRAIL-induced apoptosis requires Baxdependent mitochondrial release of Smac/DIABLO. Genes Dev.2002;16(1):33-45.
33 Ehrhardt H, Fulda S, Schmed I, et al. TRAIL induced survival and proliferation in cancer cells resistant toward TRAIL-induced apoptosis mediated by NF-kappaB[J]. Oncogene, 2003,22:3842～52
34 Shetty S,Gladden J B, Henson E S, et al.Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) up regulations death receptor5 (DR5) mediated by NF-kappaB activation in epithelial derved cell lines. Apoptosis, 2002,7(5):413～20
35 Hu Z,Tao YG,Tang FQ,et al.Effect of JIP on the proliferation and apoptosis of nasopharyngeal carcinoma cells through interaction with JNK mediated pathway[J]. Prog Biochem Biophys,2003,30(4) :579-585.
36 Chen X, Kandasamy K, Srivastava R K. Differential roles of RelA(p65) and c-Rel subunits of nuclear factor kappaB in tumor necrosis factor-relatedapoptosis-inducing ligand signaling.Cancer Res,2003,63(5):1059～66
37 Baetu TM, Kwon H, Sharma S, Grandvaux N, Hiscott J. Disruption of NF-kappaB signaling reveals a novel role for NfkappaB in the regulation of TNF-related apoptosis-inducing ligand expression. J Immunol 2001; 167: 3164-3173.
38 Koschny R, Walczak H, Ganten T. The promise of TRAILpotential and risks of a novel anticancer therapy [J]. J Mol Med, 2007, 85: 923-935.
39 Cretney E, Takeda K, Smyth MJ. Cancer: novel therapeutic strategies that exploit the TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway [J]. Int J Biochem Cell Biol, 2007, 39: 280-286.
40 Ganten TM,Koschny R,Sykora J,et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs [J]. Clin Cancer Res,2006,12:2640-1246
41 Guan B, Yue P, Clayman GL, et al. Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene [J]. J Cell Physiol, 2001, 188: 98-105.
42 Seol JW, Chaudhari AA, Lee YJ, et al. Regulation of DR-5 protein and mitochondrial transmembrane potential by gemcitabine, a possible mechanism of gemcitabine-enhanced TRAIL-induced apoptosis [J]. Oncol Rep, 2007, 18: 523-529.
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