van der Sloot Almer M, Tur Vicente, Szegezdi Eva, Mullally Margaret M, Cool Robbert H, Samali Afshin, Serrano Luis, Quax Wim J
Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8634-9. doi: 10.1073/pnas.0510187103. Epub 2006 May 26.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that selectively induces apoptosis in a variety of cancer cells by interacting with death receptors DR4 and DR5. TRAIL can also bind to decoy receptors (DcR1, DcR2, and osteoprotegerin receptor) that cannot induce apoptosis. The occurrence of DR5-responsive tumor cells indicates that a DR5 receptor-specific TRAIL variant will permit tumor-selective therapies. By using the automatic design algorithm FOLD-X, we successfully generated DR5-selective TRAIL variants. These variants do not induce apoptosis in DR4-responsive cell lines but show a large increase in biological activity in DR5-responsive cancer cell lines. Even wild-type TRAIL-insensitive ovarian cancer cell lines could be brought into apoptosis. In addition, our results demonstrate that there is no requirement for antibody-mediated cross-linking or membrane-bound TRAIL to induce apoptosis through DR5.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种潜在的抗癌药物，它通过与死亡受体DR4和DR5相互作用，选择性地诱导多种癌细胞凋亡。TRAIL也能与不能诱导凋亡的诱饵受体（DcR1、DcR2和骨保护素受体）结合。DR5反应性肿瘤细胞的出现表明，一种DR5受体特异性的TRAIL变体将允许进行肿瘤选择性治疗。通过使用自动设计算法FOLD-X，我们成功地生成了DR5选择性TRAIL变体。这些变体在DR4反应性细胞系中不诱导凋亡，但在DR5反应性癌细胞系中显示出生物学活性大幅增加。甚至野生型TRAIL不敏感的卵巢癌细胞系也能被诱导凋亡。此外，我们的结果表明，通过DR5诱导凋亡不需要抗体介导的交联或膜结合TRAIL。
