Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner.
Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner.
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DOI：
10.1158/0008-5472.can-10-2286
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Brown EJ
中科院分区：
文献类型：
--
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
先前的研究表明，致癌应激激活ATR-Chk 1通路。在这里，我们证明了ATR-Chk 1通路参与是必要的限制基因组不稳定性致癌Ras转化。ATR途径抑制与致癌Ras表达的组合协同增加基因组不稳定性，如通过染色单体断裂、姐妹染色单体交换和H2 AX磷酸化量化的。这种不稳定性水平显著高于在未转化的对照细胞中ATR抑制后观察到的水平。此外，与长期基因组维持的缺陷一致，亚形态ATR途径降低至正常水平的16%是培养细胞中致癌Ras表达的合成致死。值得注意的是，ATR抑制后基因组不稳定性和合成致死率的升高不是由于Ras转化细胞的循环速率加快，表明这些协同效应是在每个细胞周期的基础上产生的。与亚形态ATR抑制的合成致死效应相反，ATR表达的轻微降低（单倍不足）与内源性K-rasG 12 D表达水平的结合提高了p53杂合子小鼠肺腺癌、梭形细胞肉瘤和胸腺淋巴瘤的发病率。在ATR+/−p53+/−小鼠中，K-rasG 12 D诱导的肿瘤发生与染色体内缺失和野生型p53缺失相关。这些发现表明，在致癌Ras转化细胞中ATR减少后基因组不稳定性的协同增加可以产生两种不同的生物学结果：ATR表达显著抑制后的合成致死性和ATR单倍不足背景下的肿瘤促进。这些结果突出了ATR途径作为恶性进展的屏障和作为癌症治疗的潜在靶点的重要性。
Previous studies indicate that oncogenic stress activates the ATR-Chk1 pathway. Here, we demonstrate that ATR-Chk1 pathway engagement is essential for limiting genomic instability following oncogenic Ras transformation. ATR pathway inhibition in combination with oncogenic Ras expression synergistically increased genomic instability, as quantified by chromatid breaks, sister chromatid exchanges and H2AX phosphorylation. This level of instability was significantly greater than that observed following ATR suppression in untransformed control cells. In addition, consistent with a deficiency in long-term genome maintenance, hypomorphic ATR pathway reduction to 16% of normal levels was synthetic lethal with oncogenic Ras expression in cultured cells. Notably, elevated genomic instability and synthetic lethality following suppression of ATR were not due to accelerated cycling rates in Ras-transformed cells, indicating that these synergistic effects were generated on a per-cell-cycle basis. In contrast to the synthetic lethal effects of hypomorphic ATR suppression, subtle reduction of ATR expression (haploinsufficiency) in combination with endogenous levels of K-rasG12D expression elevated the incidence of lung adenocarcinoma, spindle cell sarcoma and thymic lymphoma in p53 heterozygous mice. K-rasG12D-induced tumorigenesis in ATR+/−p53+/− mice was associated with intrachromosomal deletions and loss of wild-type p53. These findings indicate that synergistic increases in genomic instability following ATR reduction in oncogenic Ras-transformed cells can produce two distinct biological outcomes: synthetic lethality upon significant suppression of ATR expression and tumor promotion in the context of ATR haploinsufficiency. These results highlight the importance of the ATR pathway both as a barrier to malignant progression and as a potential target for cancer treatment.