Ohtsuka T, Liu X-F, Koga Y, Kitajima Y, Nakafusa Y, Ha C-W, Lee S W, Miyazaki K
Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan.
Oncogene. 2006 Mar 16;25(12):1807-11. doi: 10.1038/sj.onc.1209204.
Tumor suppressor p53 is known to play a crucial role in chemosensitivity in colorectal cancer. We previously demonstrated that an apoptosis-associated speck-like protein, ASC, is a p53-target gene which regulates p53-Bax mitochondrial apoptotic pathway. ASC is also known to be a target of methylation-induced gene silencing. An inactivation of ASC might thus cause resistance to chemotherapy, and if this is the case, then the expression of ASC would restore the chemosensitivity. The aim of this study was to clarify this hypothesis. ASC was methylated in 25% of all resected specimens in patients with colorectal cancer; however, ASC methylation did not always correspond to a lack of ASC protein. When expressed in colon cancer cells, in which ASC is absent due to methylation, ASC was found to enhance the chemosensitivity in a p53-dependent manner. In p53-null cells, ASC increased the p53-mediated cell death induced by p53-expressing adenovirus infection. Our data suggest that the methylation-induced silencing of ASC might cause resistance to p53-mediated chemosensitivity in colorectal cancer. The gene introduction of ASC may thus restore such chemosensitivity, and this modality may therefore be a useful new treatment strategy for colorectal cancer.
已知肿瘤抑制因子p53在结直肠癌的化疗敏感性中起关键作用。我们之前证明，一种凋亡相关斑点样蛋白ASC是一个p53靶基因，可调节p53 - Bax线粒体凋亡途径。ASC也已知是甲基化诱导基因沉默的一个靶点。因此，ASC的失活可能导致对化疗的抗性，如果是这样，那么ASC的表达将恢复化疗敏感性。本研究的目的是阐明这一假设。在结直肠癌患者的所有切除标本中，25%存在ASC甲基化；然而，ASC甲基化并不总是与ASC蛋白的缺失相对应。当在因甲基化而不存在ASC的结肠癌细胞中表达时，发现ASC以p53依赖的方式增强化疗敏感性。在p53缺失的细胞中，ASC增加了由表达p53的腺病毒感染诱导的p53介导的细胞死亡。我们的数据表明，甲基化诱导的ASC沉默可能导致结直肠癌对p53介导的化疗敏感性产生抗性。因此，ASC的基因导入可能恢复这种化疗敏感性，并且这种方式可能因此成为结直肠癌一种有用的新治疗策略。
