p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines.
p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines.
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发表时间：
2000-11
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通讯作者：
I. Peták;D. Tillman;J. Houghton
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作者：
I. Peták;D. Tillman;J. Houghton
我们检查了在 DNA 导向（HT29、VRC5/c1 和 RKO）和 RNA 导向（HCT8 和 HCT116）细胞毒性条件下，人结肠癌细胞系接受 5-氟尿嘧啶 (FUra) 联合亚叶酸 (LV) 处理时诱导细胞凋亡的模式、Fas 表达以及 p53 肿瘤抑制基因状态的影响。在表达 wtp53（RKO、HCT8 和 HCT116）的细胞系中诱导急性凋亡，与 FUra 作用机制无关。在表达 mp53 的 HT29 细胞中，细胞凋亡是一个延迟事件。经历 DNA 指导的 FUra 细胞毒性的细胞系表现出明显的 S 期细胞积累（HT29 和 RKO），而经历 RNA 指导的细胞毒性的细胞系（HCT8 和 HCT116）表现出明显的 G2-M 期细胞周期停滞，两者均可通过 dThd 逆转。 dThd 部分保护 HCT8 和 HCT116 细胞免受 FUra-LV 诱导的细胞凋亡，但对 FUra-LV 诱导的克隆存活丧失没有影响。在表达 wtp53 的细胞中，Fas 死亡受体因 FUra-LV 处理而被诱导。 FUra-LV 使 RKO 细胞对抗 Fas 单克隆抗体 CH-11 敏感，而 dThd 完全逆转这种敏化，这表明 DNA 损伤参与了 FUra-LV 诱导的 Fas 依赖性对 CH-11 的敏化。相反，FUra-LV 使 HCT116 细胞对 CH-11 诱导的细胞凋亡敏感，这是 dThd 不可逆的。用 Ad-wtp53 转导 HT29 细胞可诱导 Fas 表达升高，并使细胞对 FUra-LV 诱导的细胞凋亡敏感。数据表明wtp53基因的存在决定FUra-LV诱导的Fas表达、FUra-LV诱导的细胞凋亡的动力学而不是诱导的细胞凋亡的程度，两者均独立于FUra作用的机制。因此，在表达wtp53的结肠癌中，FUra-LV以p53依赖性方式提高Fas表达的作用可能会进一步增强使肿瘤对Fas介导的细胞凋亡敏感的方法。
We examined the patterns of induction of apoptosis, Fas expression, and the influence of the status of the p53 tumor suppressor gene, in response to treatment of human colon carcinoma cell lines to 5-fluorouracil (FUra) combined with leucovorin (LV) under conditions of both DNA-directed (HT29, VRC5/c1, and RKO) and RNA-directed (HCT8 and HCT116) cytotoxicity. Acute apoptosis was induced in cell lines expressing wtp53 (RKO, HCT8, and HCT116), independent of the mechanism of FUra action. In HT29 cells that expressed mp53, apoptosis was a delayed event. Cell lines undergoing DNA-directed FUra cytotoxicity demonstrated marked accumulation of cells in S-phase (HT29 and RKO), whereas those lines undergoing RNA-directed cytotoxicity (HCT8 and HCT116) demonstrated marked cell cycle phase arrest in G2-M, both reversible by dThd. dThd partially protected HCT8 and HCT116 cells from FUra-LV-induced apoptosis but had no influence on FUra-LV-induced loss in clonogenic survival. In cells expressing wtp53, the Fas death receptor was induced in response to FUra-LV treatment. FUra-LV sensitized RKO cells to the anti-Fas monoclonal antibody CH-11 that was completely reversed by dThd, demonstrating the involvement of DNA damage in FUra-LV-induced, Fas-dependent sensitization to CH-11. In contrast, FUra-LV sensitized HCT116 cells to CH-11-induced apoptosis, which was not dThd reversible. Transduction of HT29 cells with Ad-wtp53 induced elevated Fas expression and sensitized the cells to FUra-LV-induced apoptosis. Data indicate that the presence of a wtp53 gene determines FUra-LV-induced Fas expression, the kinetics of FUra-LV-induced apoptosis and not the extent of apoptosis induced, both being independent of the mechanism of FUra action. Therefore, in colon carcinomas that express wtp53, the approach to sensitize tumors to Fas-mediated apoptosis may be further enhanced from the effect of FUra-LV in elevating Fas expression in a p53-dependent manner.