Abstract
Aberrant Wnt/β-catenin signaling has been strongly associated with the tumorigenesis of human colorectal cancer. Inhibitors of this pathway may then offer therapeutic strategies as well as chemoprevention for this malignant disease. Henryin is an ent-kaurane diterpenoid isolated from Isodonrubescens var. lushanensis, a plant long been used in folk medicine to prevent inflammation and gastrointestinal disease. In the present study, we report that henryin selectively inhibits the proliferation of human colorectal cancer cells with a GI50 value in the nano-molar range. Microarray analysis and reporter assays showed that henryin worked as a novel antagonist of Wnt signaling pathway. Henryin reduced the expression of Cyclin D1 and C-myc, and induced G1/S phase arrest in HCT116 cells. Concurrently, henryin did not affect the cytosol-nuclear distribution of soluble β-catenin, but impaired the association of β-catenin/TCF4 transcriptional complex likely through directly blocking the binding of β-catenin to TCF4. We also then analyzed the structure-activity relationship among the ent-kaurane type diterpenoids. Our data suggests that henryin, as a novel inhibitor of Wnt signaling, could be a potential candidate for further preclinical evaluation for colon cancer treatment, and as such warrants further exploration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Diterpenes, Kaurane / chemistry
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Diterpenes, Kaurane / pharmacology*
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Dose-Response Relationship, Drug
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G1 Phase Cell Cycle Checkpoints / drug effects
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G1 Phase Cell Cycle Checkpoints / genetics
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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HT29 Cells
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Humans
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Molecular Structure
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Oligonucleotide Array Sequence Analysis
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Protein Binding / drug effects
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Protein Binding / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Structure-Activity Relationship
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Time Factors
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Wnt Signaling Pathway / drug effects*
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Wnt Signaling Pathway / genetics
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Diterpenes, Kaurane
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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beta Catenin
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henryin
Grants and funding
This work was supported by both the 100 Talents Program (YL) and the West Light Foundation (JP) of the Chinese Academy of Sciences, the Major State Basic Research Development Program of China (No. 2009CB522300), the Natural Science Foundation of China (No.81173076, 81172939), and the Recruited Top Talent of Sciences and Technology of Yunnan Province (2009C1120), China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.