OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The cytotoxicity of a potent Cyclophilin A(CypA)inhibitor HL001 was tasted against a p...OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The 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.RESULTS We 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 p53wildtype 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.CONCLUSION Pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.展开更多
TP53, encoding a well-known tumor suppressor p53, plays essential roles in tumor initiation and pro- gression, and is frequently mutated in lung cancer. However, pharmacological stabilization and reactivation of p53 h...TP53, encoding a well-known tumor suppressor p53, plays essential roles in tumor initiation and pro- gression, and is frequently mutated in lung cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Here, we identified 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, and further stabilizes p53 through inhibiting the MDM2-mediated p53 ubiqutination. The down-regulation of G3BP1 by HL001 also contributes to p53 stabilization by inhibiting p53 redistribution from nucleus to cytoplasm. Furthermore, HE001 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-de- pendent manner. Finally, administration of HE001 alone or co-treatment with cisplatin promotes significant tumor suppression in orthotopic NSCLC mouse model. Collectively, our preclinical study demonstrated that HE001, a small molecule inhibitor of CypA, selectively activated p53WT 72R homozygote and thus inhibits growth of human lung cancer cells. The results presented here demonstrate that the utility of CypA inhibitors serve as an approach to the targeted therapy for individual lung cancer patient.展开更多
基金supported by National Natural Science Foundation of China(31371485,81402482,91313303 and 81573020)CAS Key Laboratory of Receptor Research,the Shanghai Committee of Science and Technology(15431902000)
文摘OBJECTIVE To explored the potential of pharmacological stabilization and reactivation of p53 for targeted cancer therapies.METHODS The 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.RESULTS We 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 p53wildtype 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.CONCLUSION Pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.
文摘TP53, encoding a well-known tumor suppressor p53, plays essential roles in tumor initiation and pro- gression, and is frequently mutated in lung cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Here, we identified 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, and further stabilizes p53 through inhibiting the MDM2-mediated p53 ubiqutination. The down-regulation of G3BP1 by HL001 also contributes to p53 stabilization by inhibiting p53 redistribution from nucleus to cytoplasm. Furthermore, HE001 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-de- pendent manner. Finally, administration of HE001 alone or co-treatment with cisplatin promotes significant tumor suppression in orthotopic NSCLC mouse model. Collectively, our preclinical study demonstrated that HE001, a small molecule inhibitor of CypA, selectively activated p53WT 72R homozygote and thus inhibits growth of human lung cancer cells. The results presented here demonstrate that the utility of CypA inhibitors serve as an approach to the targeted therapy for individual lung cancer patient.
