Yu Hong-Pei, Xie Jia-Ming, Li Bin, Sun Yi-Hui, Gao Quan-Geng, Ding Zhi-Hui, Wu Hao-Rong, Qin Zheng-Hong
Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Department of General Surgery, the First People's Hospital of Wu Jiang, Suzhou 215004, China.
Sci Rep. 2015 Apr 30;5:9853. doi: 10.1038/srep09853.
Previous study revealed that the protective effect of TIGAR in cell survival is mediated through the increase in PPP (pentose phosphate pathway) flux. However, it remains unexplored if TIGAR plays an important role in DNA damage and repair. This study investigated the role of TIGAR in DNA damage response (DDR) induced by genotoxic drugs and hypoxia in tumor cells. Results showed that TIGAR was increased and relocated to the nucleus after epirubicin or hypoxia treatment in cancer cells. Knockdown of TIGAR exacerbated DNA damage and the effects were partly reversed by the supplementation of PPP products NADPH, ribose, or the ROS scavenger NAC. Further studies with pharmacological and genetic approaches revealed that TIGAR regulated the phosphorylation of ATM, a key protein in DDR, through Cdk5. The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR defines a new role of TIGAR in cancer cell survival and it suggests that TIGAR may be a therapeutic target for cancers.
先前的研究表明，TIGAR对细胞存活的保护作用是通过增加磷酸戊糖途径（PPP）通量来介导的。然而，TIGAR在DNA损伤和修复中是否发挥重要作用仍未得到探索。本研究调查了TIGAR在肿瘤细胞中由基因毒性药物和缺氧诱导的DNA损伤反应（DDR）中的作用。结果显示，在癌细胞中，表柔比星或缺氧处理后，TIGAR增加并重新定位到细胞核。敲低TIGAR会加剧DNA损伤，而补充PPP产物NADPH、核糖或活性氧清除剂NAC可部分逆转这些效应。通过药理学和遗传学方法的进一步研究表明，TIGAR通过Cdk5调节DDR中的关键蛋白ATM的磷酸化。TIGAR参与调节DDR的Cdk5-ATM信号通路定义了TIGAR在癌细胞存活中的新作用，这表明TIGAR可能是癌症的治疗靶点。
