机构：[1]College of Biology, Hunan University, Changsha 410082, China[2]Departmentof Gastroenterology, The Tenth People’s Hospital of Shanghai, TongjiUniversity, Shanghai 200072, China[3]Department of Laboratory Medicine,Xiangya School of Medicine, Central South University, Changsha 410013, China[4]Shenzhen Institute, Hunan University, Shenzhen, China[5]Department of Outpatient,Affiliated Hospital of Hebei University of Engineering, Handan 056002,China
Colon cancer is one of the three common malignant tumors, with a lower survival rate. Ipatasertib, a novel highly selective ATP-competitive pan-Akt inhibitor, shows a strong antitumor effect in a variety of carcinoma, including colon cancer. However, there is a lack of knowledge about the precise underlying mechanism of clinical therapy for colon cancer. We conducted this study to determine that ipatasertib prevented colon cancer growth through PUMA-dependent apoptosis. Ipatasertib led to p53-independent PUMA activation by inhibiting Akt, thereby activating both FoxO3a and NF-κB synchronously that will directly bind to PUMA promoter, up-regulating PUMA transcription and Bax-mediated intrinsic mitochondrial apoptosis. Remarkably, Akt/FoxO3a/PUMA is the major pathway while Akt/NF-κB/PUMA is the secondary pathway of PUMA activation induced by ipatasertib in colon cancer. Knocking out PUMA eliminated ipatasertib-induced apoptosis both in vitro and in vivo (xenografts). Furthermore, PUMA is also indispensable in combinational therapies of ipatasertib with some conventional or novel drugs. Collectively, our study demonstrated that PUMA induction by FoxO3a and NF-κB is a critical step to suppress the growth of colon cancer under the therapy with ipatasertib, which provides some theoretical basis for clinical assessment.
基金：
We would like to thank the support of the Fundamental Research Funds for
the Central Universities (Nos. 531107040909 and 14700-502044001), the Basic
Research Program of Shenzhen Municipal Science and Technology Innovation
Committee (JCYJ20160530192802733), the National Natural Science
Foundation of China (31701132), and the start funds from College of Biology,
Hunan University.
第一作者机构：[1]College of Biology, Hunan University, Changsha 410082, China[5]Department of Outpatient,Affiliated Hospital of Hebei University of Engineering, Handan 056002,China
通讯作者：
通讯机构：[1]College of Biology, Hunan University, Changsha 410082, China[2]Departmentof Gastroenterology, The Tenth People’s Hospital of Shanghai, TongjiUniversity, Shanghai 200072, China[4]Shenzhen Institute, Hunan University, Shenzhen, China
推荐引用方式(GB/T 7714)：
Li Sun,Yuan Huang,Yeying Liu,et al.Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis.[J].CELL DEATH & DISEASE.2018,9:911.doi:10.1038/s41419-018-0943-9.
APA：
Li Sun,Yuan Huang,Yeying Liu,Yujie Zhao,Xiaoxiao He...&Yingjie Zhang.(2018).Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis..CELL DEATH & DISEASE,9,
MLA：
Li Sun,et al."Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis.".CELL DEATH & DISEASE 9.(2018):911
生物学