Exp Mol Med.  2009 Oct;41(10):717-727. 10.3858/emm.2009.41.10.078.

Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression

Affiliations
  • 1Department of Pharmacology, School of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Shaanxi Province 710032, China. qbmei@fmmu.edu.cn
  • 2State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Shaanxi Province 710032, China. fandmdmfan@yahoo.com.cn
  • 3Protein Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen 2200, Denmark.

Abstract

Triptolide, a diterpenoid triepoxide from the traditional Chinese medicinal herb Tripterygium wilfordii Hook. f., is a potential treatment for autoimmune diseases as well a possible anti-tumor agent. It inhibits proliferation of coloretal cancer cells in vitro and in vivo. In this study, its ability to block progress of colitis to colon cancer, and its molecular mechanism of action are investigated. A mouse model for colitis-induced colorectal cancer was used to test the effect of triptolide on cancer progression. Treatment of mice with triptolide decreased the incidence of colon cancer formation, and increased survival rate. Moreover, triptolide decreased the incidence of tumors in nude mice inoculated with cultured colon cancer cells dose-dependently. In vitro, triptolide inhibited the proliferation, migration and colony formation of colon cancer cells. Secretion of IL6 and levels of JAK1, IL6R and phosphorylated STAT3 were all reduced by triptolide treatment. Triptolide prohibited Rac1 activity and blocked cyclin D1 and CDK4 expression, leading to G1 arrest. Triptolide interrupted the IL6R-JAK/STAT pathway that is crucial for cell proliferation, survival, and inflammation. This suggests that triptolide might be a candidate for prevention of colitis induced colon cancer because it reduces inflammation and prevents tumor formation and development.

Keyword

colonic neoplasms; interleukin-6; rac1 GTP-binding protein; STAT3 transcription factor; triptolide

MeSH Terms

Animals
Cell Transformation, Neoplastic/*drug effects
Colitis/complications
Colonic Neoplasms/chemically induced/*drug therapy/metabolism/pathology
Dextran Sulfate/toxicity
Dimethylhydrazines/toxicity
Diterpenes/*administration & dosage
Epoxy Compounds/administration & dosage
Humans
Interleukin-6/biosynthesis
Janus Kinases/metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred ICR
Mice, Nude
Neoplasm Transplantation
Phenanthrenes/*administration & dosage
STAT3 Transcription Factor/metabolism
Signal Transduction/*drug effects
Tumor Burden/drug effects
rac1 GTP-Binding Protein/*biosynthesis
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