Garcinone C Suppresses Tumorsphere Formation and Invasiveness by Hedgehog/Gli1 Signaling in Colorectal Cancer Stem-like Cells
- Authors
- Zhou, Yimeng; Qiu, Shuai; Kim, Jin Tae; Lee, Seung Beom; Park, Ho Jin; Son, Moon Jeong; Lee, Hong Jin; Chen, Jing
- Issue Date
- Jul-2022
- Publisher
- AMER CHEMICAL SOC
- Keywords
- garcinone C; colorectal cancer stem-like cell; invasiveness; Gli1; molecular docking
- Citation
- JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, v.70, no.26, pp 7941 - 7952
- Pages
- 12
- Journal Title
- JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
- Volume
- 70
- Number
- 26
- Start Page
- 7941
- End Page
- 7952
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/68561
- DOI
- 10.1021/acs.jafc.2c01891
- ISSN
- 0021-8561
1520-5118
- Abstract
- Hyperactivation of hedgehog signaling occurs in colorectal cancer stem-like cells (CSCs), a rare subpopulation, potentially involved in metastasis, chemotherapy resistance, and cancer relapse. Garcinone C, a xanthone isolated from mangosteen (Garcinia mangostana), suppresses colorectal cancer in vivo and in vitro by inhibiting Gli1-dependent noncanonical hedgehog signaling. Herein, we investigated the effect of garcinone C on cancer stemness and invasiveness in colorectal cancer; Gli1 was noted as pivotal in maintaining stemness and invasiveness in HCT116 and HT29 CSCs. Garcinone C inhibited the proliferation and self-renewal of HCT116 and HT29 CSCs. Colon cancer stemness markers such as CD44, CD133, ALDH1, and Nanog were significantly decreased by garcinone C. Computational studies showed that garcinone C showed a high affinity with the Gli1 protein ZF domain by forming hydrogen bonds with amino acid residues of ASP244, ARG223, and ASP216. Besides, MG132 blocked the effects of garcinone C on Gli1. Thus, garcinone C suppressed colorectal CSCs by binding to Gli1 and enhancing its degradation. MMP2 and MMP9 levels, invasive-related markers, were increased in HCT116 CSCs but decreased by garcinone C. E-cadherin level was reduced in HCT116 CSCs, while the presence of garcinone C was restored. Garcinone C inhibited the proliferation and invasiveness of colorectal CSCs by targeting Gli1-dependent Hh signaling. Garcinone C may be a potent natural agent against colorectal cancer relapse.
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