Department of Food Science and Biotechnology, Chung-Ang University, Anseong 17546, South Korea.
Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou 510632, China.
J Agric Food Chem. 2022 Jul 6;70(26):7941-7952. doi: 10.1021/acs.jafc.2c01891. Epub 2022 Jun 24.
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 (), suppresses colorectal cancer and 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.
hedgehog 信号的过度激活发生在结直肠肿瘤干细胞（CSCs）中，CSCs 是一种罕见的亚群，可能与转移、化疗耐药和癌症复发有关。从山竹果（）中分离得到的黄烷酮 garcinone C 可抑制 Gli1 依赖性非经典 hedgehog 信号通路，从而抑制结直肠癌。在此，我们研究了 garcinone C 对结直肠癌细胞干性和侵袭性的影响；Gli1 被认为是维持 HCT116 和 HT29 CSCs 干性和侵袭性的关键。Garcinone C 抑制了 HCT116 和 HT29 CSCs 的增殖和自我更新。结直肠肿瘤干性标志物如 CD44、CD133、ALDH1 和 Nanog 被 garcinone C 显著下调。计算研究表明，garcinone C 与 Gli1 蛋白 ZF 结构域具有高亲和力，通过与 ASP244、ARG223 和 ASP216 氨基酸残基形成氢键。此外，MG132 阻断了 garcinone C 对 Gli1 的作用。因此，garcinone C 通过与 Gli1 结合并增强其降解来抑制结直肠 CSCs。MMP2 和 MMP9 水平，侵袭相关标志物，在 HCT116 CSCs 中增加，但被 garcinone C 降低。E-cadherin 水平在 HCT116 CSCs 中降低，而 garcinone C 的存在恢复了这一水平。Garcinone C 通过靶向 Gli1 依赖性 Hh 信号通路抑制结直肠 CSCs 的增殖和侵袭。Garcinone C 可能是一种有效的天然抗结直肠癌复发药物。
