机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China[2]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China[3]State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China[4]Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA[5]CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China[6]Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA[7]Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA[8]Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA[9]Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA[10]Center for Complex Networks Research, Northeastern University, Boston, MA, USA.
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 wild-type 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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [21222211, 31371485, 81402482, 91313303, 81573020]; CAS Key Laboratory of Receptor Research; Shanghai Committee of Science and TechnologyShanghai Science & Technology Committee [14ZR1411100, 15431902000]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2014M551361, 2015T80415]
语种：
外文
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区医学
小类|1 区遗传学2 区生化与分子生物学2 区细胞生物学2 区肿瘤学
最新[2023]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区遗传学2 区细胞生物学2 区肿瘤学
第一作者：
第一作者机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China[2]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China[*1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237 China.
推荐引用方式(GB/T 7714)：
W Lu,F Cheng,W Yan,et al.Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA.[J].Oncogene.2017,36(33):4719-4731.doi:10.1038/onc.2017.41.
APA：
W Lu,F Cheng,W Yan,X Li,X Yao...&J Huang.(2017).Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA..Oncogene,36,(33)
MLA：
W Lu,et al."Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA.".Oncogene 36..33(2017):4719-4731
医学