Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, The Netherlands.
J Pathol. 2011 Feb;223(3):378-89. doi: 10.1002/path.2797. Epub 2010 Oct 29.
TNF-related apoptosis-inducing ligand (TRAIL) receptor agonistic agents and non-steroidal anti-inflammatory drugs (NSAIDs) are interesting agents for the chemoprevention and treatment of colorectal cancer. We investigated whether NSAIDs sensitize colon cancer and adenoma cell lines and ex vivo cultured human adenomas to recombinant human (rh)TRAIL. Involvement of the crucial Wnt signalling pathway in the sensitization of colon cancer cells was examined. Five colon cancer and two adenoma cell lines, human ex vivo adenomas and normal colonic epithelium were treated with aspirin or sulindac combined with rhTRAIL. Apoptosis levels, expression of intracellular proteins and TRAIL receptor membrane expression were assessed. Ls174T cells stably transfected with an inducible dominant negative TCF-4 (dnTCF-4) construct served to analyse the role of Wnt pathway activation. Both rhTRAIL-sensitive and -resistant colon cancer cell lines were strongly sensitized to rhTRAIL by aspirin (maximum enhancement ratio, 7.1). Remarkably, in adenoma cell lines sulindac enhanced rhTRAIL-induced apoptosis most effectively (maximum enhancement ratio, 2.5). Although membrane TRAIL receptor expression was not affected by NSAIDs, caspase-8 activation was enhanced by combinational treatment. Several proteins from different biological pathways were affected by NSAIDs, indicating complex mechanisms of sensitization. Elimination of TCF-4 completely blocked the sensitizing effect in colon cancer cells. In ex vivo adenomas the combination of sulindac and rhTRAIL increased apoptosis from 18.4% (sulindac) and 17.8% (rhTRAIL) to 28.0% (p = 0.003 and p = 0.005, respectively). It was concluded that NSAID-induced sensitization to rhTRAIL requires TCF-4 activity. Thus, the combination of TRAIL-receptor agonistic agents and NSAIDs is a potentially attractive treatment option for (pre)malignant tumours with constitutively active Wnt signalling, such as colorectal tumours.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体激动剂和非甾体抗炎药（NSAIDs）是结直肠癌化学预防和治疗的有前途的药物。我们研究了 NSAIDs 是否能使结肠癌和腺瘤细胞系以及体外培养的人腺瘤对重组人（rh）TRAIL 敏感。检测了关键 Wnt 信号通路在结肠癌细胞敏化中的作用。用阿司匹林或舒林酸联合 rhTRAIL 处理五种结肠癌和两种腺瘤细胞系、人体外腺瘤和正常结肠上皮。评估细胞凋亡水平、细胞内蛋白表达和 TRAIL 受体膜表达。使用稳定转染诱导型显性负性 TCF-4（dnTCF-4）构建体的 Ls174T 细胞用于分析 Wnt 途径激活的作用。阿司匹林（最大增强比为 7.1）强烈增强了 rhTRAIL 敏感和不敏感的结肠癌细胞系对 rhTRAIL 的敏感性。值得注意的是，在腺瘤细胞系中，舒林酸最有效地增强了 rhTRAIL 诱导的凋亡（最大增强比为 2.5）。尽管 NSAIDs 不影响膜 TRAIL 受体表达，但联合治疗增强了 caspase-8 激活。几种来自不同生物途径的蛋白质受 NSAIDs 影响，表明敏化的复杂机制。消除 TCF-4 完全阻断了结肠癌细胞的敏化作用。在体外腺瘤中，舒林酸和 rhTRAIL 的联合使用将凋亡从 18.4%（舒林酸）和 17.8%（rhTRAIL）增加到 28.0%（p=0.003 和 p=0.005）。结论是 NSAID 诱导的 rhTRAIL 敏感性需要 TCF-4 活性。因此，TRAIL 受体激动剂和 NSAIDs 的联合使用是一种有吸引力的治疗选择，用于治疗具有组成性激活的 Wnt 信号的（前）恶性肿瘤，如结直肠肿瘤。
