Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair-deficient Colorectal Cancer Cells
Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair-deficient Colorectal Cancer Cells
复制标题
DOI：
10.1091/mbc.e09-04-0303
复制
发表时间：
2009-09-01
影响因子：
3.3
通讯作者：
Wang, Xiao-Fan
中科院分区：
文献类型：
--
作者：
Jardim, Melanie J.;Wang, Qinhong;Wang, Xiao-Fan
结直肠癌的基因组不稳定性分为两类：染色体不稳定性（CIN）和微卫星不稳定性（MSI）。MSI是错配修复（MMR）机制突变的结果，而CIN通常被认为与APC基因的破坏有关。最近的临床数据显示，在人类癌症中存在ATR和Chk 1杂合突变，这些突变表现为MSI，表明这些突变可能有助于肿瘤发生。为了确定DNA损伤检查点途径的活性降低是否会与MMR缺陷协同诱导CIN，我们使用siRNA策略部分降低MMR缺陷型结直肠癌细胞中ATR或Chk 1的表达。所得的癌细胞显示典型的CIN表型，其特征在于染色体异常数量的增加。重要的是，MMR能力的恢复完全抑制了CIN表型的诱导，表明部分检查点阻断和MMR缺陷的组合是触发CIN所必需的。此外，ATR和Chk 1在MMR缺陷细胞中的破坏增强了对常用的结肠直肠化疗化合物5-氟尿嘧啶治疗的敏感性。这些结果为这些癌症患者的联合治疗的发展提供了基础。
Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients.