Huang,CS (reprint author),NYU,Sch Med,Nelson Inst Environm Med,57 Old Forge Rd,Tuxedo Pk,NY 10987 USA.
Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. (C)2014 AACR.
1.NYU, Sch Med, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA 2.Wenzhou Med Univ, Sch Life Sci, Zhejiang Prov Key Lab Technol & Applicat Model Or, Wenzhou, Zhejiang, Peoples R China 3.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Peoples R China 4.Chinese Acad Sci, Kunming Inst Bot, Kunming, Peoples R China
Zhu, Junlan,Zhang, Jingjie,Huang, Haishan,et al. Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation[J]. CANCER PREVENTION RESEARCH,2014,7(12):1270-1281.