文献类型：期刊文献

英文题名：SoNar, a Highly Responsive NAD+/NADH Sensor, Allows High-Throughput Metabolic Screening of Anti-tumor Agents

作者：Zhao, Yuzheng[1,2,3,4];Hu, Qingxun[1];Cheng, Feixiong[4];Su, Ni[1,2,4];Wang, Aoxue[1,2,4];Zou, Yejun[1,2,4];Hu, Hanyang[1];Chen, Xianjun[1,2,4];Zhou, Hai-Meng[5];Huang, Xinzhi[6];Yang, Kai[6];Zhu, Qian[1,2];Wang, Xue[1];Yi, Jing[6];Zhu, Linyong[7];Qian, Xuhong[8];Chen, Lixin[9];Tang, Yun[4];Loscalzo, Joseph[10];Yang, Yi[1,2,3,4]

机构：[1]E China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg Technol, Synth Biol & Biotechnol Lab, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]E China Univ Sci & Technol, CAS Ctr Excellence Brain Sci, Optogenet & Mol Imaging Interdisciplinary Res Ctr, Shanghai 200237, Peoples R China;[3]E China Univ Sci & Technol, Collaborat Innovat Ctr Genet & Dev, Shanghai 200237, Peoples R China;[4]E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[5]Tsinghua Univ, Yangtze Delta Reg Inst, Zhejiang Prov Key Lab Appl Enzymol, Jiaxing 314006, Peoples R China;[6]Shanghai Jiao Tong Univ, Dept Biochem & Mol Cell Biol, Educ Minist Cell Differentiat & Apoptosis, Key Lab,Inst Med Sci,Sch Med, Shanghai 200025, Peoples R China;[7]E China Univ Sci & Technol, Inst Fine Chem, Key Lab Adv Mat, Shanghai 200237, Peoples R China;[8]E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[9]Chinese Acad Sci, Shanghai Lab Anim Ctr, Shanghai 201615, Peoples R China;[10]Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

年份：2015

卷号：21

期号：5

起止页码：777

外文期刊名：CELL METABOLISM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000353978700019)】；

基金：We thank Gary Yellen for the Peredox vector; Jim Remington for the roGFP vector; Jiahuai Han for the cDNA of Enox and Nox families; Hongbin Ji, Jianwen Liu, Jing Zheng, Ping Shi, Xuni Cao, Zhaoyang Ye, and Jia Yu for different cell lines; Guiping Li, Qiongyu Yan, Chunyuan Zhou, Qiuning Lin, Lei Xu, Rongkun Tao, Jianhua Wang, Zhengda Chen, and Wei Wang for technical assistance; and Stephanie Tribuna for secretarial assistance. This work was supported by the 973 Program (2013CB531200), NSFC (91313301, 31225008, 31071260, 31170815, 31470833, and 91013012), Specialized Research Fund for the Doctoral Program of Higher Education (20100074110010), Shanghai Science and Technology Commission (12JC1402900, 11DZ2260600, 15YF1402600), Dawn Program of the Shanghai Education Commission (11SG31), State Key Laboratory of Bioreactor Engineering, the 111 Project (B07023), and the Fundamental Research Funds for the Central Universities, as well as NIH grants (to J.L.) HL061795, HL048743, and HL108630.

语种：英文

摘要：The altered metabolism of tumor cells confers a selective advantage for survival and proliferation, and studies have shown that targeting such metabolic shifts may be a useful therapeutic strategy. We developed an intensely fluorescent, rapidly responsive, pH-resistant, genetically encoded sensor of wide dynamic range, denoted SoNar, for tracking cytosolic NAD(+) and NADH redox states in living cells and in vivo. SoNar responds to subtle perturbations of various pathways of energy metabolism in real time, and allowed high-throughput screening for new agents targeting tumor metabolism. Among > 5,500 unique compounds, we identified KP372-1 as a potent NQO1-mediated redox cycling agent that produced extreme oxidative stress, selectively induced cancer cell apoptosis, and effectively decreased tumor growth in vivo. This study demonstrates that genetically encoded sensor-based metabolic screening could serve as a valuable approach for drug discovery.