Selective targeting p53WTlung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

Wei-qiang LU,Qian HU,Jian LI,Jin HUANG

(Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China）

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Selective targeting p53WTlung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA

Wei-qiang LU,Qian HU,Jian LI,Jin HUANG

(Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China）

OBJECTIVETo explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODSThe cytotoxicity of a potent Cyclophilin A(CypA)inhibitor HL001 was tasted against a panel of cancer cell lines.The genotypes and activation of p53 were compared with the cytotoxicity profile of HL001.Two-dimensional(2D)PAGE analysis was performed to investigate differentially expressed proteins that involves in the anti-proliferation effects of HL001.Pull-down and Co-IP were used to confirmed the new identified PPI between CypA and G3BP1 and orthotopic animal model of lung cancer was used to tested the anti-tumor activity of HL001 in vivo.RESULTSWe identify a novel 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.CONCLUSIONPharma?cologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.

non-small cell lung cancer;Cyclophilin A inhibitor;p53-72R polymorphsm

The project supported by National Natural Science Foundation of China(31371485,81402482,91313303 and 81573020);and CAS Key Laboratory of Receptor Research,the Shanghai Committee of Science and Technology(15431902000)

Jin HUANG,E-amil:huangjin@ecust.edu.cn;jian LI,E-maii:jianli@ecust.edu.cn