Garcinone C 通过 Hedgehog/Gli1 信号传导抑制结直肠癌干细胞样细胞中的肿瘤球形成和侵袭,Journal of Agricultural and Food Chemistry

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Garcinone C 通过 Hedgehog/Gli1 信号传导抑制结直肠癌干细胞样细胞中的肿瘤球形成和侵袭
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2022-06-24 , DOI: 10.1021/acs.jafc.2c01891
Yimeng Zhou ₁ , Shuai Qiu ₁ , Jin Tae Kim ₁ , Seung Beom Lee ₁ , Ho Jin Park ₁ , Moon Jeong Son ₁ , Hong Jin Lee ₁ , Jing Chen ₂

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刺猬信号的过度激活发生在结直肠癌干细胞样细胞 (CSC) 中，这是一种罕见的亚群，可能与转移、化疗耐药和癌症复发有关。Garcinone C 是一种从山竹 ( Garcinia mangostana ) 中分离出来的黄酮，可在体内和体外抑制结肠直肠癌通过抑制 Gli1 依赖的非经典刺猬信号。在此，我们研究了garcinone C对结直肠癌干性和侵袭性的影响；Gli1 被认为是维持 HCT116 和 HT29 CSCs 的干性和侵袭性的关键。Garcinone C 抑制 HCT116 和 HT29 CSCs 的增殖和自我更新。garcinone C 显着降低结肠癌干性标志物如 CD44、CD133、ALDH1 和 Nanog。计算研究表明，garcinone C 通过与 ASP244、ARG223、和 ASP216。此外，MG132阻断了garcinone C对Gli1的影响。因此，garcinone C 通过与 Gli1 结合并增强其降解来抑制结肠直肠 CSC。MMP2 和 MMP9 水平，侵袭性相关标志物，在 HCT116 CSCs 中增加，但由 garcinone C 降低。HCT116 CSCs 中 E-钙粘蛋白水平降低，而 garcinone C 的存在恢复。Garcinone C 通过靶向 Gli1 依赖性 Hh 信号传导抑制结直肠 CSCs 的增殖和侵袭。Garcinone C 可能是对抗结直肠癌复发的有效天然药物。

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Garcinone C Suppresses Tumorsphere Formation and Invasiveness by Hedgehog/Gli1 Signaling in Colorectal Cancer Stem-like Cells

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.

更新日期：2022-06-24

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