Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells
Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells
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DOI：
10.1158/0008-5472.can-04-1909
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
McConkey, DJ
中科院分区：
文献类型：
--
作者：
Papageorgiou, A;Lashinger, L;McConkey, DJ
免疫调节剂如卡介苗和干扰素在膀胱移行细胞癌中具有临床活性，但其作用机制尚不清楚。在此，我们研究了ifna - α对20个人膀胱癌细胞系肿瘤坏死因子相关凋亡诱导配体（TRAIL）表达和凋亡的影响。6例（30%）在增加IFNa浓度（10-100,000单位/mL）时显示出明显的DNA断裂。在这些细胞系中，ifn - α诱导caspase-8的早期激活，并且DNA片段被caspase-8选择性抑制剂（IETDfmk）阻断，这与死亡受体参与细胞死亡相一致。在大多数ifn敏感和ifn耐药细胞系中，ifn - α刺激TRAIL mRNA和蛋白的显著增加。在六种ifn敏感细胞系中，有四种具有阻断性抗TRAIL抗体，可显著抑制ifn诱导的DNA断裂，证实TRAIL在细胞死亡中起直接作用。硼替佐米（PS-341, Velcade）是一种有效的TRAIL增敏剂，在两种IFN耐药细胞系中增加了对IFN- α的敏感性，这些细胞系在IFN治疗后产生了大量TRAIL。我们的数据显示，ifn诱导的膀胱癌细胞凋亡通常涉及自分泌TRAIL的产生。旨在克服TRAIL耐药性的联合治疗策略可能非常有效地恢复人类膀胱肿瘤亚群中IFN的敏感性。
Immunomodulators such as Bacillus Calmette-Guerin and interferon are clinically active in transitional cell carcinoma of the bladder, but their mechanisms of action remain unclear. Here we investigated the effects of IFNalpha on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and apoptosis in a panel of 20 human bladder cancer cell lines. Six (30%) displayed significant DNA fragmentation in response to increasing concentrations of IFNa (10-100,000 units/mL). In these lines IFNalpha induced early activation of caspase-8, and DNA fragmentation was blocked by a caspase-8-selective inhibitor (IETDfmk), consistent with the involvement of death receptor(s) in cell death. IFNalpha stimulated marked increases in TRAIL mRNA and protein in the majority of IFN-sensitive and IFN-resistant cell lines. A blocking anti-TRAIL antibody significantly inhibited IFN-induced DNA fragmentation in four of six IFN-sensitive cell lines, confirming that TRAIL played a direct role in cell death. Bortezomib (PS-341, Velcade), a potent TRAIL-sensitizing agent, increased sensitivity to IFNalpha in two of the IFN-resistant cell lines that produced large amounts of TRAIL in response to IFN treatment. Our data show that IFN-induced apoptosis in bladder cancer cells frequently involves autocrine TRAIL production. Combination therapy strategies aimed at overcoming TRAIL resistance may be very effective in restoring IFN sensitivity in a subset of human bladder tumors.