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Hydrogen peroxide/ATR-Chk2 activation mediates p53 protein stabilization and anti-cancer activity of cheliensisin A in human cancer cells.

Abstract
Chiliensisine A (Chel A) as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu has been indicated to be a chemotherapeutic agent in Leukemia HL-60 cells. However, its potential for cancer treatment and the underlying mechanisms are not deeply investigated to the best of our knowledge. Current studies showed that Chel A could trigger p53-mediated apoptosis, accompanied with dramatically inhibition of anchorage-independent growth of human colon cancer HCT116 cells. Further studies found that Chel A treatment resulted in p53 protein stabilization and accumulation via the induction of its phosphorylation at Ser20 and Ser15. Moreover, Chel A-induced p53 protein accumulation and activation required ATR/Chk2 axis, which is distinct from the mechanism that we have most recently identified the Chk1/p53-dependent apoptotic response by Chel A in normal mouse epidermal Cl41 cells. In addition, our results demonstrated that hydrogen peroxide generation induced by Chel A acted as a precursor for all these signaling events and downstream biological effects. Taken together, we have identified the Chel A as a new therapeutic agent, which highlights its potential for cancer therapeutic effect.
AuthorsJingjie Zhang, Guangxun Gao, Liang Chen, Jingxia Li, Xu Deng, Qin-shi Zhao, Chuanshu Huang
JournalOncotarget (Oncotarget) Vol. 5 Issue 3 Pg. 841-52 (Feb 15 2014) ISSN: 1949-2553 [Electronic] United States
PMID24553354 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Epoxy Compounds
  • Pyrones
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • cheliensisin A
  • Hydrogen Peroxide
  • Checkpoint Kinase 2
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
Topics
  • Apoptosis (drug effects)
  • Ataxia Telangiectasia Mutated Proteins (genetics, metabolism)
  • Checkpoint Kinase 2 (genetics, metabolism)
  • Colonic Neoplasms (drug therapy, metabolism, pathology)
  • Epoxy Compounds (pharmacology)
  • HCT116 Cells
  • Humans
  • Hydrogen Peroxide (metabolism)
  • Pyrones (pharmacology)
  • Signal Transduction
  • Transfection
  • Tumor Suppressor Protein p53 (genetics, metabolism)
  • Tumor Suppressor Proteins (genetics, metabolism)

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