ATR mediates cisplatin resistance in a p53 genotype-specific manner.
ATR mediates cisplatin resistance in a p53 genotype-specific manner.
复制标题
DOI：
10.1038/onc.2010.624
复制
发表时间：
2011-06-02
期刊：
影响因子：
8
通讯作者：
Bunz, F.
中科院分区：
文献类型：
--
作者：
Sangster-Guity, N.;Conrad, B. H.;Papadopoulos, N.;Bunz, F.
共济失调-毛细血管扩张和RAD3相关(ATR)基因编码的蛋白激酶被DNA损伤剂激活，而DNA损伤剂经常被用作抗癌治疗。抑制ATR在培养的癌细胞中的表达已被证明增加了对化疗药物的敏感性，包括DNA交联剂顺铂。顺铂是一种广泛使用的有效药物，但它的使用与显著的毒性有关。在这里，我们证明了ATR表达的遗传抑制选择性地增强了具有失活P53的人结直肠癌细胞对顺铂的敏感性。使用敲打策略在含有野生型或突变型ATR等位基因的细胞中恢复野生型p53。ATR缺陷细胞中功能性P53的切开恢复了检查点功能，抑制了凋亡途径，并显著提高了顺铂治疗后的克隆性存活率。这些结果表明，将ATR的特定抑制剂与传统疗法相结合的策略可能会提高p53缺陷肿瘤的合成致死率，同时将对正常组织的毒性降至最低。
The protein kinase encoded by the ataxia-telangiectasia and Rad3-related (ATR) gene is activated by DNA damaging agents that are frequently employed as anticancer therapeutics. Inhibition of ATR expression in cultured cancer cells has been demonstrated to increase sensitivity to chemotherapeutic drugs, including the DNA crosslinking agent cisplatin. Cisplatin is a widely employed and effective drug, but its use is associated with significant toxicity. Here, we demonstrate that genetic inhibition of ATR expression selectively enhanced cisplatin sensitivity in human colorectal cancer cells with inactivated p53. A knockin strategy was employed to restore wild type p53 in cells harboring wild type or mutant ATR alleles. Knockin of functional p53 in ATR-deficient cells restored checkpoint function, suppressed apoptotic pathways, and dramatically increased clonogenic survival after cisplatin treatment. These results suggest that a strategy that combines specific inhibitors of ATR and conventional therapies might promote synthetic lethality in p53-deficient tumors while minimizing toxicity to normal tissues.
登录
查看更多内容
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
5.3
作者：
Kodama, Masami;Otsubo, Chihiro;Taya, Yoichi
通讯作者：
Taya, Yoichi
影响因子：
4.3
作者：
Hurley, Paula J.;Bunz, Fred
通讯作者：
Bunz, Fred
影响因子：
64.5
作者：
Oda, K;Arakawa, H;Taya, Y
通讯作者：
Taya, Y