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 Isodon rubescens 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.
Highlights
Colorectal cancer (CRC) is a common malignancy that, despite advancements in drug treatment and improved diagnosis, remains a major challenge to the medical establishment world-wide
Henryin selectively inhibits the growth of colorectal cancer cells and induces G1 phase arrest of the cell cycle
Analysis of the GI50 values of henryin and cisplatin on the different cell lines supported the observation that henryin had a selective inhibitory effect on colon cancer cells (Figure 1D)
Summary
Colorectal cancer (CRC) is a common malignancy that, despite advancements in drug treatment and improved diagnosis, remains a major challenge to the medical establishment world-wide. According to recent reports from the Cancer Genome Atlas Network, the Wnt pathway is constitutively activated in over 90% of human colorectal cancer by both genetic and epigenetic alterations to a number of genes that are involved in the Wnt signaling pathway, such as β-catenin, APC and Axin2 [7]. Activation of Wnt/β-catenin signaling subsequently increases the expression of Wnt target genes, such as Cyclin D1 [8], C-myc [9] and Survivin [10], all of which are involved in cell proliferation, apoptosis and cell cycle deregulation in the development and progression of malignant colorectal cancer phenotypes [11,12,13]
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