Lin Hung-Yun, Sun Mingzeng, Tang Heng-Yuan, Simone Tessa M, Wu Yun-Hsuan, Grandis Jennifer R, Cao H James, Davis Paul J, Davis Faith B
Signal Transduction Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208, USA.
J Cell Biochem. 2008 Aug 15;104(6):2131-42. doi: 10.1002/jcb.21772.
Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro-apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene-induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells.
环氧化酶-2（COX-2）在多种肿瘤细胞中的含量会增加。我们研究了白藜芦醇（一种在许多肿瘤细胞系中具有促凋亡作用的芪类化合物）通过涉及细胞COX-2的机制诱导人头颈鳞状细胞癌UMSCC-22B细胞凋亡的机制。对用白藜芦醇处理24小时的UMSCC-22B细胞（有无选择的抑制剂）进行了检测：（1）检测核内活化的ERK1/2、p53和COX-2的存在情况；（2）检测凋亡证据；（3）通过染色质免疫沉淀法证明p53与p21启动子的结合。芪类化合物诱导的凋亡呈浓度依赖性，并与ERK1/2活化、丝氨酸-15位点的p53磷酸化以及这些蛋白的核内积累相关。ERK1/2或p53活化的抑制可阻断这些作用。白藜芦醇还导致p53与p21启动子结合，并增加UMSCC-22B细胞核中COX-2蛋白的丰度。白藜芦醇诱导的核COX-2积累依赖于ERK1/2活化，但不依赖于p53活化。COX-2抑制剂NS398以及用COX-2小干扰RNA转染细胞可阻断p53的活化和p53依赖性凋亡。在UMSCC-22B细胞中，白藜芦醇诱导的凋亡和核COX-2积累的诱导均依赖于ERK1/2信号转导通路。白藜芦醇诱导的COX-2核内积累对于这些癌细胞中p53的活化和p53依赖性凋亡至关重要。
