Garcinone C suppresses colon tumorigenesis through the Gli1-dependent hedgehog signaling pathway |
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| Institution: | 1. Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany;2. Pharmacognosy Area, Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 531, Rosario 2000, Argentina;1. College of Pharmacy, Guilin Medical University, 541004 Guilin, China;2. Research Center for Science, Guilin Medical University, Guilin 541004, China;3. Xiangya Hospital, Central South University, 410008 Changsha, China;4. Intensive Care Unit, Zhuzhou Central Hospital, 412007 Zhuzhou, China;5. Digestive System Department, The Frist People''s Hospital of Yueyang, 414000 Yueyang, China;6. The Frist hospital of Fuzhou, 350000 Fuzhou, China;1. Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea;2. Interdisciplinary Program in Agricultural Genomics, Seoul National University, Seoul 08826, Republic of Korea;3. Department of Agricultural Biotechnology, Center for Food and Bioconvergence, and Research Institute of Agriculture and Life Sciences, CALS, Seoul National University, Seoul 08826, Republic of Korea;4. Department of Food Science and Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea |
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| Abstract: | BackgroundAlthough garcinone C, a natural xanthone derivative identified in the pericarp of Garcinia mangostana, has been demonstrated to exert different health beneficial activities in oxidative stress and β-amyloid aggregation, the role of garcinone C in colon tumorigenesis has not been investigated. In addition, aberrant Hedgehog (Hh) signaling activation is associated with tumorigenesis including colon cancer. Here, we hypothesized that garcinone C can prevent colon tumorigenesis through regulating the Hh signaling pathway.MethodColony formation assay and flow cytometry were used to evaluate the effect of garcinone C on the proliferation and cell cycle progression of colon cancer cells. Protein expression of cell cycle related markers and Hh/Gli1 signaling mediators were determined. The regulatory effect of orally administered garcinone C on the Hh/Gli1 signaling pathway and colon tumorigenesis was evaluated in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer animal model.ResultsGarcinone C suppressed the proliferation of colon cancer cells, induced G0/G1 cell cycle arrest, as well as regulated the expression of cell cycle-related markers such as cyclin D1, cyclin E, CDK6, and p21. Garcinone C inhibited the expression of Gli1, a key mediator of Hedgehog signaling, and protein kinase B (AKT) phosphorylation in Smo-independent colon cancer cells. In the AOM/DSS-induced colon tumorigenesis model, garcinone C significantly inhibited tumor development, regulated the expression of cell cycle markers and Gli1, and reduced AKT phosphorylation in colon tumor tissues, which is consistent with our in vitro results.ConclusionGarcinone C can suppress colon tumorigenesis in vitro and in vivo through Gli1-dependent non-canonical Hedgehog signaling, suggesting that it may serve as a potent chemopreventive agent against colon tumorigenesis. |
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