Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer
Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer
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DOI：
10.1158/0008-5472.can-05-0961
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Johnston, PG
中科院分区：
文献类型：
--
作者：
McDermott, U;Longley, DB;Johnston, PG
我们研究了p53和转录信号转换器和激活因子1 （STAT 1）在调节fas介导的结直肠癌化疗后细胞凋亡中的作用。我们发现5-氟尿嘧啶（5-FU）和奥沙利铂仅使p53野生型（WT）结直肠癌细胞株对fas介导的凋亡敏感。相比之下，伊立替康（CPT-11）和托莫地克斯使p53 WT、突变和空细胞对fas介导的细胞死亡敏感。此外，CPT-11和tomudex，而不是5-FU或奥沙利铂，以p53不依赖的方式上调Fas细胞表面表达。此外，在CPT-11和tomudex的作用下，p53突变细胞株和无突变细胞株中Fas细胞表面表达增加，但Fas mRNA和蛋白表达总量仅略有增加，这表明这些药物触发了不依赖于p53的Fas向质膜运输。CPT-11或tomudex在p53缺失的HCT116细胞系中诱导STAT1磷酸化（Ser(727)），但在p53 WT细胞系中没有。此外，stat1靶向小干扰RNA （siRNA）抑制Fas细胞表面表达上调，以响应CPT-11和tomudex。然而，在药物处理的细胞中，我们没有发现sirna介导的STAT1下调后Fas基因表达改变的证据。这表明STAT1在CPT-11或tomudex的作用下调控参与细胞表面Fas转运的基因表达。我们得出结论，CPT-11和tomudex可能比5-FU和奥沙利铂更有效地治疗p53突变型结直肠癌肿瘤，使其以stat1依赖的方式对fas介导的凋亡敏感。
We investigated the role of p53 and the signal transducer and activator of transcription 1 (STAT 1) in regulating Fas-mediated apoptosis in response to chemotherapies used to treat colorectal cancer. We found that 5-fluorouracil (5-FU) and oxaliplatin only sensitized p53 wild-type (WT) colorectal cancer cell lines to Fas-mediated apoptosis. In contrast, irinotecan (CPT-11) and tomudex sensitized p53 WT, mutant, and null cells to Fas-mediated cell death. Furthermore, CPT-11 and tomudex, but not 5-FU or oxaliplatin, up-regulated Fas cell surface expression in a p53-independent manner. In addition, increased Fas cell surface expression in p53 mutant and null cell lines in response to CPT-11 and tomudex was accompanied by only a slight increase in total Fas mRNA and protein expression, suggesting that these agents trigger p53-independent trafficking of Fas to the plasma membrane. Treatment with CPT-11 or tomudex induced STAT1 phosphorylation (Ser(727)) in the p53-null HCT116 cell line but not the p53 WT cell line. Furthermore, STAT1-targeted small interfering RNA (siRNA) inhibited up-regulation of Fas cell surface expression in response to CPT-11 and tomudex in these cells. However, we found no evidence of altered Fas gene expression following siRNA-mediated downregulation of STAT1 in drug-treated cells. This suggests that STAT1 regulates expression of gene(s) involved in cell surface trafficking of Fas in response to CPT-11 or tomudex. We conclude that CPT-11 and tomudex may be more effective than 5-FU and oxaliplatin in the treatment of p53 mutant colorectal cancer tumors by sensitizing them to Fas-mediated apoptosis in a STAT1-dependent manner.