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Cheliensisin A inhibits EGF-induced cell transformation with stabilization of p53 protein via a hydrogen peroxide/Chk1-dependent axis.

Abstract
Cheliensisin A (Chel A), a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been shown to induce apoptosis in human promyelocytic leukemia HL-60 cells with Bcl-2 downregulation. Yet, the potential chemopreventive effect of Chel A has not been explored. Here, we showed that Chel A treatment with various concentrations (0.5, 1.0, 2.0, and 4.0 μmol/L) for 3 weeks could dramatically inhibit EGF-induced cell transformation in Cl41 cells (IC50 ∼2.0 μmol/L). Also, coincubation of Cl41 cells with Chel A (2.0 and 4.0 μmol/L) for 48 hours could induce cell apoptosis in a caspase-3-dependent manner. Mechanically, Chel A treatment could result in increased p53 phosphorylation at Ser15 and elevated p53 total protein expression. Moreover, we found that p53 induction by Chel A was regulated at the protein degradation level, but not at either the transcription or the mRNA level. Further studies showed that p53 stabilization by Chel A was mediated via induction of phosphorylation and activation of Chk1 protein at Ser345. This notion was substantiated by the results that transfection of dominant negative mutant of Chk1 (GFP-Chk1 D130A) significantly attenuated the p53 protein expression, cell apoptosis, and inhibition of cell transformation by Chel A. Finally, increased hydrogen peroxide was found to mediate Chk1 phosphorylation at Ser345, p53 protein induction, cell apoptotic induction, and transformation inhibition following Chel A treatment. Taken together, our studies identify Chel A as a chemopreventive agent with the understanding of the molecular mechanisms involved.
AuthorsJingjie Zhang, Guangxun Gao, Liang Chen, Xu Deng, Jingxia Li, Yonghui Yu, Dongyun Zhang, Fei Li, Min Zhang, Qinshi Zhao, Chuanshu Huang
JournalCancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 6 Issue 9 Pg. 949-58 (Sep 2013) ISSN: 1940-6215 [Electronic] United States
PMID23852422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Epoxy Compounds
  • Oxidants
  • Pyrones
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • cheliensisin A
  • Epidermal Growth Factor
  • Hydrogen Peroxide
  • Protein Kinases
  • Checkpoint kinase 1
Topics
  • Animals
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Proliferation (drug effects)
  • Cell Transformation, Neoplastic (drug effects, metabolism, pathology)
  • Cells, Cultured
  • Epidermal Growth Factor (pharmacology)
  • Epidermis (cytology, drug effects, metabolism)
  • Epoxy Compounds (pharmacology)
  • Flow Cytometry
  • Humans
  • Hydrogen Peroxide (pharmacology)
  • Mice
  • Oxidants (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Kinases (metabolism)
  • Protein Stability (drug effects)
  • Proteolysis (drug effects)
  • Pyrones (pharmacology)
  • RNA, Messenger (genetics)
  • Reactive Oxygen Species (metabolism)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Tumor Suppressor Protein p53 (chemistry, genetics, metabolism)

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