National University of Ireland, Galway, National Centre for Biomedical Engineering Science (NCBES), Galway, Ireland, Molecular Therapeutics Group, Galway, Ireland.
Cancer Lett. 2012 Mar 28;316(2):168-77. doi: 10.1016/j.canlet.2011.10.035. Epub 2011 Nov 2.
The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a specific and potent inducer of apoptosis in cancer cells, but the resistance of many tumour cells to TRAIL still represents a major hurdle for the clinical treatment of tumours with TRAIL. As apoptosis is regulated by the balance of activities of several anti-apoptotic factors and pro-apoptotic factors, we analysed the relative contribution of the two sides and found that down-regulation of Bcl-x(L) and in particular XIAP, but not c-Flip, sensitised the TRAIL resistant pancreatic cancer cell line Panc-1. A combination of both XIAP and Bcl-x(L) knock-downs showed no substantial added benefit indicating that both act in the same pathway. Notably, the degree of sensitisation by silencing of anti-apoptotic genes was further elevated by concomitantly increasing the pro-apoptotic potential in Panc-1 cells through over-expression of TRAIL-R1 or IFN-γ-mediated increases in caspase-8 levels. Similar sensitisation effects were obtained for another TRAIL-resistant pancreatic tumour cell line, AsPC-1. Our findings demonstrate that modulation of the balance between anti- and pro-apoptotic pathways from both sides by inhibition of apoptosis-antagonists and stimulation of pro-apoptotic factors provides the best way to enhance the anti-tumourigenic effect of TRAIL.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种特异性和有效的诱导癌细胞凋亡的物质，但许多肿瘤细胞对 TRAIL 的抵抗仍然是 TRAIL 治疗肿瘤的主要障碍。由于细胞凋亡受到几种抗凋亡因子和促凋亡因子活性平衡的调节，我们分析了双方的相对贡献，发现下调 Bcl-x(L)，特别是 XIAP，但不是 c-Flip，可使 TRAIL 耐药的胰腺癌细胞系 Panc-1 敏感化。XIAP 和 Bcl-x(L) 的双重敲除并没有显示出实质性的额外益处，这表明它们在同一途径中起作用。值得注意的是，通过沉默抗凋亡基因来增加促凋亡潜能，通过 TRAIL-R1 的过表达或 IFN-γ 介导的 caspase-8 水平增加，可进一步提高通过沉默抗凋亡基因来增加敏感性。对于另一种 TRAIL 耐药的胰腺肿瘤细胞系 AsPC-1，也获得了类似的敏感化效果。我们的研究结果表明，通过抑制凋亡拮抗剂和刺激促凋亡因子来调节抗凋亡和促凋亡途径之间的平衡，为增强 TRAIL 的抗肿瘤作用提供了最佳途径。
