Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression.
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 colorectal 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.
Wang
Zhipeng
Z
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Shaanxi Province 710032, China.
Jin
Haifeng
H
Xu
Ruodan
R
Mei
Qibing
Q
Fan
Daiming
D
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003092:Colitis / Q000150:complications; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004127:Dimethylhydrazines / Q000633:toxicity; D004224:Diterpenes / Q000008:administration & dosage*; D004852:Epoxy Compounds / Q000008:administration & dosage; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010616:Phenanthrenes / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis*
D004127:Dimethylhydrazines; D004224:Diterpenes; D004852:Epoxy Compounds; D015850:Interleukin-6; D010616:Phenanthrenes; D050796:STAT3 Transcription Factor; C001899:triptolide; D016264:Dextran Sulfate; D053612:Janus Kinases; D020830:rac1 GTP-Binding Protein