Zeng Dequan, Zhang Lipen, Luo Qiang
Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.
Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, China.
Front Pharmacol. 2023 Feb 15;14:1124240. doi: 10.3389/fphar.2023.1124240. eCollection 2023.
Celastrol, a triterpene derived from (; Celastraceae), a traditional Chinese herb, has promising anticancer activity. The present study aimed to elucidate an indirect mechanism of celastrol-mediated alleviation of hepatocellular carcinoma (HCC) gut microbiota-regulated bile acid metabolism and downstream signaling. Here, we constructed a rat model of orthotopic HCC and performed 16S rDNA sequencing and UPLC-MS analysis. The results showed that celastrol could regulate gut bacteria; suppress the abundance of ; raise the levels of glycoursodeoxycholic acid (GUDCA), a bile acid; and alleviate HCC. We found that GUDCA suppressed cellular proliferation and induced the arrest of mTOR/S6K1 pathway-associated cell cycle G0/G1 phase in HepG2 cells. Further analyses using molecular simulations, Co-IP, and immunofluorescence assays revealed that GUDCA binds to farnesoid X receptor (FXR) and regulates the interaction of FXR with retinoid X receptor (RXRα). Transfection experiments using the FXR mutant confirmed that FXR is essential for GUCDA-mediated suppression of HCC cellular proliferation. Finally, animal experiments showed that the treatment with the combination of celastrol/GUDCA alleviated the adverse effects of celastrol alone treatment on body weight loss and improved survival in rats with HCC. In conclusion, the findings of this study suggest that celastrol exerts an alleviating effect on HCC, in part regulation of the -GUDCA-FXR/RXRα-mTOR axis.
雷公藤红素是一种从传统中药（卫矛科）中提取的三萜类化合物，具有良好的抗癌活性。本研究旨在阐明雷公藤红素介导的肝细胞癌（HCC）缓解的间接机制，即肠道微生物群调节胆汁酸代谢及下游信号传导。在此，我们构建了原位HCC大鼠模型，并进行了16S rDNA测序和超高效液相色谱-质谱分析。结果表明，雷公藤红素可调节肠道细菌；抑制[具体细菌名称未给出]的丰度；提高胆汁酸甘氨熊去氧胆酸（GUDCA）的水平；并缓解HCC。我们发现GUDCA抑制细胞增殖，并诱导HepG2细胞中mTOR/S6K1通路相关的细胞周期G0/G1期停滞。使用分子模拟、免疫共沉淀和免疫荧光分析的进一步研究表明，GUDCA与法尼酯X受体（FXR）结合，并调节FXR与视黄醇X受体（RXRα）的相互作用。使用FXR突变体的转染实验证实，FXR对于GUDCA介导的HCC细胞增殖抑制至关重要。最后，动物实验表明，雷公藤红素/GUDCA联合治疗减轻了雷公藤红素单独治疗对体重减轻的不利影响，并提高了HCC大鼠的生存率。总之，本研究结果表明，雷公藤红素对HCC具有缓解作用，部分是通过调节[具体细菌名称未给出]-GUDCA-FXR/RXRα-mTOR轴实现的。
