Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
Cell Death Dis. 2013 Jul 4;4(7):e702. doi: 10.1038/cddis.2013.214.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine and a selective inducer of apoptosis in a range of tumour cells, but not in normal, untransformed cells. A large number of chemotherapeutics as well as biological agents are being tested for their potential to sensitise resistant tumour cells to TRAIL as a means to broaden the range of tumours treatable with TRAIL. However, because of the incomplete understanding of the mechanism(s) underlying TRAIL resistance in non-malignant cells, it is unpredictable whether the effect of these sensitisers will be restricted to tumour cells or they would also sensitise non-transformed cells causing unwanted toxicity. In this study, we carried out a systematic analysis of the mechanisms driving TRAIL resistance in non-transformed cells. We found that cellular FLICE-like inhibitory protein, anti-apoptotic B-cell lymphoma 2 proteins, and X-linked inhibitor of apoptosis protein were independently able to provide resistance to TRAIL. Deficiency of only one of these proteins was not sufficient to elicit TRAIL sensitivity, demonstrating that in non-transformed cells multiple pathways control TRAIL resistance and they act in a redundant manner. This is contrary to the resistance mechanisms found in tumour cell types, many of them tend to rely on a single mechanism of resistance. Supporting this notion we found that 76% of TRAIL-resistant cell lines (13 out of 17) expressed only one of the above-identified anti-apoptotic proteins at a high level (≥1.2-fold higher than the mean expression across all cell lines). Furthermore, inhibition or knockdown of the single overexpressed protein in these tumour cells was sufficient to trigger TRAIL sensitivity. Therefore, the redundancy in resistance pathways in non-transformed cells may offer a safe therapeutic window for TRAIL-based combination therapies where selective sensitisation of the tumour to TRAIL can be achieved by targeting the single non-redundant resistance pathway.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种细胞因子，能够在多种肿瘤细胞中选择性诱导细胞凋亡，但不会在正常的未转化细胞中诱导凋亡。目前正在测试大量的化疗药物和生物制剂，以评估它们作为 TRAIL 的增敏剂的潜力，以扩大可通过 TRAIL 治疗的肿瘤范围。然而，由于对非恶性细胞中 TRAIL 耐药的机制不完全了解，因此尚无法预测这些增敏剂的作用是否仅限于肿瘤细胞，或者它们是否也会使未转化的细胞变得敏感，从而导致不必要的毒性。在这项研究中，我们对非转化细胞中驱动 TRAIL 耐药的机制进行了系统分析。我们发现，细胞 FLICE 样抑制蛋白、抗凋亡 B 细胞淋巴瘤 2 蛋白和 X 连锁凋亡抑制蛋白都能够独立地提供 TRAIL 耐药性。这些蛋白中只有一种的缺失不足以引起 TRAIL 敏感性，这表明在非转化细胞中，多个通路控制 TRAIL 耐药性，并且它们以冗余的方式发挥作用。这与肿瘤细胞类型中发现的耐药机制相反，其中许多机制往往依赖于单一的耐药机制。支持这一观点，我们发现，76%的 TRAIL 耐药细胞系（17 个中的 13 个）仅高表达上述鉴定的一种抗凋亡蛋白（比所有细胞系的平均表达水平高≥1.2 倍）。此外，在这些肿瘤细胞中抑制或敲低单个过表达的蛋白足以触发 TRAIL 敏感性。因此，非转化细胞中耐药通路的冗余性可能为基于 TRAIL 的联合治疗提供了一个安全的治疗窗口，通过靶向单一非冗余的耐药通路，可以选择性地使肿瘤对 TRAIL 敏感。
