Papageorgiou Angela, Lashinger Laura, Millikan Randall, Grossman H Barton, Benedict William, Dinney Colin P N, McConkey David J
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Cancer Res. 2004 Dec 15;64(24):8973-9. doi: 10.1158/0008-5472.CAN-04-1909.
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 IFNalpha (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.
诸如卡介苗和干扰素之类的免疫调节剂在膀胱移行细胞癌中具有临床活性，但其作用机制仍不清楚。在此，我们研究了α干扰素对20种人膀胱癌细胞系中肿瘤坏死因子相关凋亡诱导配体（TRAIL）表达及凋亡的影响。六种（30%）细胞系在α干扰素浓度增加（10 - 100,000单位/毫升）时出现显著的DNA片段化。在这些细胞系中，α干扰素诱导半胱天冬酶-8的早期激活，并且DNA片段化被半胱天冬酶-8选择性抑制剂（IETDfmk）阻断，这与死亡受体参与细胞死亡一致。α干扰素在大多数对干扰素敏感和耐药的细胞系中刺激TRAIL mRNA和蛋白显著增加。一种阻断性抗TRAIL抗体在六种对干扰素敏感的细胞系中的四种中显著抑制了干扰素诱导的DNA片段化，证实TRAIL在细胞死亡中起直接作用。硼替佐米（PS - 341，万珂），一种有效的TRAIL增敏剂，在两种对干扰素耐药的细胞系中增加了对α干扰素的敏感性，这两种细胞系在接受干扰素治疗时产生大量TRAIL。我们的数据表明，干扰素诱导的膀胱癌细胞凋亡经常涉及自分泌TRAIL的产生。旨在克服TRAIL耐药性的联合治疗策略可能在恢复一部分人膀胱肿瘤对干扰素的敏感性方面非常有效。
