The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation  

作　　者：Wu-li Zhao Yan Xing Cheng Ye Yu-han Qiu Yi Li Xiu-jun Liu Meng-yan Wang Chong-wen Bi Dan-qing Song Rong-guang Shao 

机构地区：[1]Key Laboratory of Antibiotic Bioengineering,Ministry of Health,Laboratory of Oncology,Institute of Medicinal Biotechnology,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing 100050,China [2]Department of Pediatrics,Peking University Third Hospital,Beijing 100083,China

出　　处：《Acta Pharmacologica Sinica》2020年第5期686-697,共12页中国药理学报（英文版）

基　　金：the National Key Research and Development Program of China(2016YFA0201504);National Natural Science Foundation of China(Nos.81473249 and 81102464);the National Mega-project for Innovative Drugs(2014ZX09201042);the CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-2-002);Drug Innovation Major Project of China(2018ZX09711001-007-002).

摘　　要：Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out,and the potent anticancer compound IMB-HDC was acquired.Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage,the underlying mechanisms of inhibition of DNA damage repair(ATR inactivation)and the apoptosis independent of p53,have not been elucidated.Our research reveals a novel DNA response mechanism different from general DNA-damaging agents,and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus,and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation,thus inhibiting ATR activation.Meanwhile,IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis.More importantly,we give thefirst evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

关 键 词：DNA breakage STAT5a SHUTTLE ANTICANCER nuclear location 

分 类 号：R96[医药卫生—药理学]