第1周
癌症研究
DNA损伤
生物
细胞凋亡
癌细胞
合成致死
肺癌
DNA修复
癌症
细胞周期
细胞生物学
DNA
医学
生物化学
遗传学
病理
细胞周期蛋白依赖激酶1
作者
Guo Chen,Beilei Zhang,Haiyang Xu,Yao Sun,Yaru Shi,Yichen Luo,Haiying Jia,Fu Wang
出处
期刊:Oncogene
[Springer Nature]
日期:2017-09-04
卷期号:36 (50): 6863-6872
被引量:57
摘要
Lung cancer treatment remains a challenge for clinical practice and new therapeutic approaches are urgently needed. Loss of functional WEE1 kinase causes DNA replication stress, DNA damage and unscheduled mitotic entry due to elevated CDK activity. The selective WEE1 inhibitor MK-1775 synergize with DNA-damaging agent to inhibit cancer cell growth. Here we report that inhibition of Sirt1 deacetylase through small interfering RNA or selective inhibitor Ex527 greatly enhances MK-1775-induced growth inhibition and apoptosis in human lung cancer cells. We further demonstrate that Sirt1 interacts and deacetylates homologous recombination (HR) repair machinery proteins, including NBS1 and Rad51. Inhibition of Sirt1 impairs HR repair activity, which causes unrepairable damage when combining MK-1775 and Ex527. Meanwhile, combination of MK-1775 and Ex527 induces cooperative antitumor activity in lung cancer xenograft model in vivo. Thus, our study provides a novel therapeutic strategy to optimize MK-1775 treatment efficiency in lung cancers.
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