Cheng Jinrong, Hylander Bonnie L, Baer Maria R, Chen Xing, Repasky Elizabeth A
Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Mol Cancer Ther. 2006 Jul;5(7):1844-53. doi: 10.1158/1535-7163.MCT-06-0050.
Targeting death receptors with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the remarkable potential to selectively kill malignant cells whereas normal cells are largely unaffected by this treatment. However, some tumor cells, including leukemia cells, exhibit resistance to this molecule. To investigate the basis for resistance of leukemia cells to the zinc-bound form of Apo2 ligand (Apo2L)/TRAIL, which is currently being evaluated in clinical trial, we isolated several resistant HL60 clones from parental HL60 cells by selection using the recombinant Apo2L/TRAIL. Differing resistance mechanisms were identified and characterized in these Apo2L/TRAIL-resistant clones. In one case, the level of the cell-surface death receptor DR4, but not DR5, was significantly decreased. However, these cells did undergo apoptosis in response to another form of recombinant TRAIL, histidine-tagged TRAIL, suggesting differing contributions of DR4 and DR5 in the response to these two forms of TRAIL. In the case of other clones, expression of procaspase-8 protein was lost and this was associated with a novel Leu(22)-->Phe(22) point mutation in CASP-8 gene. These results show that cells within a given tumor can have widely distinct mechanisms underlying resistance to Apo2L/TRAIL.
用肿瘤坏死因子相关凋亡诱导配体（TRAIL）靶向死亡受体具有选择性杀死恶性细胞的巨大潜力，而正常细胞在很大程度上不受这种治疗的影响。然而，一些肿瘤细胞，包括白血病细胞，对这种分子表现出抗性。为了研究白血病细胞对锌结合形式的Apo2配体（Apo2L）/TRAIL（目前正在临床试验中进行评估）产生抗性的基础，我们通过使用重组Apo2L/TRAIL进行筛选，从亲代HL60细胞中分离出几个抗性HL60克隆。在这些对Apo2L/TRAIL具有抗性的克隆中鉴定并表征了不同的抗性机制。在一种情况下，细胞表面死亡受体DR4的水平显著降低，但DR5没有。然而，这些细胞确实会对另一种形式的重组TRAIL（组氨酸标记的TRAIL）产生凋亡反应，这表明DR4和DR5在对这两种形式的TRAIL的反应中具有不同的作用。在其他克隆的情况下，procaspase-8蛋白的表达缺失，这与CASP-8基因中的一个新的Leu(22)-->Phe(22)点突变有关。这些结果表明，给定肿瘤内的细胞对Apo2L/TRAIL产生抗性的潜在机制可能有很大差异。
