Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA.

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Lu W,Cheng F,Yan W,Li X,Yao X,Song W,Liu M,Shen X,Jiang H,Chen J,Li J,Huang J

doi

10.1038/onc.2017.41

subject

Has Abstract

pub_date

2017-08-17 00:00:00

pages

4719-4731

issue

33

eissn

0950-9232

issn

1476-5594

pii

onc201741

journal_volume

36

pub_type

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