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A novel mechanism of indole-3-carbinol effects on breast carcinogenesis involves induction of Cdc25A degradation.

Abstract
The natural compound indole-3-carbinol (I3C; found in vegetables of the genus Brassica) is a promising cancer prevention or therapy agent. The cell division cycle 25A (Cdc25A) phosphatase is overexpressed in a variety of human cancers and other diseases. In the present study, I3C induced degradation of Cdc25A, arrest of the G(1) cell cycle, and inhibition of the growth of breast cancer cells. We also showed that the Ser124 site of Cdc25A, which is related to cyclin-dependent kinase 2, is required for I3C-induced degradation of Cdc25A in breast cancer cells, and that interruption of the ATM-Chk2 pathway suppressed I3C-induced destruction of Cdc25A. Our in vivo studies of different mutated forms of Cdc25A found that the mutation Cdc25A(S124A) (Ser124 to Ala124), which confers resistance to I3C-induced degradation of Cdc25A, attenuated I3C inhibition of breast tumorigenesis in a mouse xenograft model. The present in vitro and in vivo studies together show that I3C-induced activation of the ATM-Chk2 pathway and degradation of Cdc25A represent a novel molecular mechanism of I3C in arresting the G(1) cell cycle and inhibiting the growth of breast cancer cells. The finding that I3C induces Cdc25A degradation underscores the potential use of this agent for preventing and treating cancers and other human diseases with Cdc25A overexpression.
AuthorsYongsheng Wu, Xiaoling Feng, Yucui Jin, Zhaojia Wu, William Hankey, Carolyn Paisie, Lei Li, Fengjuan Liu, Sanford H Barsky, Weiwei Zhang, Ramesh Ganju, Xianghong Zou
JournalCancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 3 Issue 7 Pg. 818-28 (Jul 2010) ISSN: 1940-6215 [Electronic] United States
PMID20587702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright2010 AACR.
Chemical References
  • Anticarcinogenic Agents
  • Indoles
  • indole-3-carbinol
  • cdc25 Phosphatases
Topics
  • Animals
  • Anticarcinogenic Agents (pharmacology)
  • Breast Neoplasms (enzymology)
  • Cell Line
  • Female
  • Humans
  • Indoles (pharmacology)
  • Mice
  • Mice, Inbred BALB C
  • Signal Transduction (drug effects)
  • cdc25 Phosphatases (metabolism)

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