文献类型：期刊文献

英文题名：Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

作者：Lu, W.[1,2,3];Cheng, F.[4,5,11,12];Yan, W.[1];Li, X.[1];Yao, X.[1];Song, W.[6];Liu, M.[2,3];Shen, X.[1,7];Jiang, H.[1,7];Chen, J.[6,8,9,10];Li, J.[1];Huang, J.[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai, Peoples R China;[3]East China Univ Sci & Technol, Sch Life Sci, Shanghai, Peoples R China;[4]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu, Sichuan, Peoples R China;[5]Collaborat Innovat Ctr Biotherapy, Chengdu, Sichuan, Peoples R China;[6]Vanderbilt Univ, Sch Med, Vet Affairs Med Ctr, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA;[7]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai, Peoples R China;[8]Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA;[9]Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37212 USA;[10]Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA;[11]Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA USA;[12]Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA

年份：2017

卷号：36

期号：33

起止页码：4719

外文期刊名：ONCOGENE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000407702400005)】；

基金：We are grateful to Mr Lianbiao Cheng, Miss Jiaqian Pu and Miss Ningning Dong (all from Jin Huang lab) for material and intellectual help with the design and execution of some of these experiments. The authors thank Professor Jose M Cuezva (Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid, Madrid, Spain) for providing G3BP1 plasmid; Professor Xiangshi Tan (Department of Chemistry, Fudan University, Shanghai, China) for providing the pMAL-c2x-derived MBPHT-Cherry2 vector; Professor Yi Yang (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China) for providing H23, H838, H1703 and H2126 lung cancer cell lines. The work is supported by the National Natural Science Foundation of China (21222211, 31371485, 81402482, 91313303 and 81573020), CAS Key Laboratory of Receptor Research, the Shanghai Committee of Science and Technology (14ZR1411100 and 15431902000), China Postdoctoral Science Foundation Grant (2014M551361 and 2015T80415).

语种：英文

摘要：TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization. Surprisingly, HL001 selectively suppresses tumor growth in p53 wildtype NSCLC harboring Arg72 homozygous alleles (p53-72R) through disrupting interaction between MDM2 and p53-72R in a CypA-dependent manner. Moreover, combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model. Collectively, this study demonstrates that pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.