Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA
Year: 2017
Type: article
Abstract: 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.
Source: Oncogene
DOI: 10.1038/onc.2017.41
Institutions: East China University of Science and Technology, East China Normal University, Sichuan University, West China Hospital of Sichuan University, State Key Laboratory of Biotherapy, Vanderbilt University, VA Tennessee Valley Healthcare System, Vanderbilt University Medical Center, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Vanderbilt-Ingram Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,990
Funders: Centro de Biología Molecular Severo Ochoa, National Natural Science Foundation of China, China Postdoctoral Science Foundation, East China University of Science and Technology, Fudan University, Universidad Autónoma de Madrid, Shanghai Key Laboratory of New Drug Design, CAS Key Laboratory of Receptor Research
OpenAlex ID: W2606454898