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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

Authors: Wu-li Zhao1, Yan Xing2, Cheng Ye1, Yu-han QiuYiLi1, Xiu-jun Liu1, Meng-yan Wang1, Chong-wen Bi1, Dan-qing Song1, Rong-guang Shao2
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
Correspondence to: Dan-qing Song: songdanqing@imb.pumc.edu.cn,
DOI: 10.1038/s41401-019-0333-6
Received: 8 July 2019
Accepted: 18 November 2019
Advance online: 13 January 2020

Abstract

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 the first 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.
Keywords: DNA breakage; STAT5a; shuttle; anticancer; nuclear location

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