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Dual Targeting of Cell Growth and Phagocytosis by Erianin for Human Colorectal Cancer.
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-08-12 , DOI: 10.2147/dddt.s259006 Yihan Sun 1 , Guofeng Li 1 , Qi Zhou 1 , Danyue Shao 2 , Jingwei Lv 3 , Jianhua Zhou 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-08-12 , DOI: 10.2147/dddt.s259006 Yihan Sun 1 , Guofeng Li 1 , Qi Zhou 1 , Danyue Shao 2 , Jingwei Lv 3 , Jianhua Zhou 1
Affiliation
Objective: To investigate the effect of erianin on tumor growth and immune response in human colorectal cancer cells (CRC).
Methods: The effect of erianin on tumor growth was determined by CCK8 and colony formation assay. Western blotting was used to evaluate the expression levels of relevant proteins and qRT-PCR was used to evaluate the mRNA level of the relevant gene. The transcriptional activity of β-catenin was determined by dual-luciferase reporter assay. Cellular thermal shift assay was used to quantify drug–target interactions. The cell surface CD47 was assessed by flow cytometry. The enrichment of H3K27 acetyl marks on CD47 promoter was evaluated by chromatin immunoprecipitation assay. Phagocytosis assay was used to determine the phagocytic activity of macrophage. In vivo role of erianin was studied on xenograft models.
Results: We found that erianin significantly decreased cell survival, colony formation, induced cell cycle arrest, and led to cell apoptosis in SW480 and HCT116 cells. Mechanism analysis demonstrated that erianin inhibited the nuclear translocation and transcriptional activity of β-catenin, which might result from erianin-β-catenin interaction. In addition, the downstream gene expressions, such as c-Myc and cyclin D1, was decreased. More interestingly, erianin decreased the expression of CD47 by regulating H3K27 acetyl marks enrichment on CD47 promoter. Consequently, macrophage-mediated phagocytosis was increased. Our in vivo experiments further confirmed the inhibitory effect of erianin on tumor growth.
Conclusion: In summary, erianin could inhibit CRC cells growth and promoted phagocytosis, which suggested erianin as a potential therapeutic strategy for CRC patients.
Keywords: erianin, colorectal cancer, β-catenin, CD47, macrophage
中文翻译：
Erianin 对人类结直肠癌的细胞生长和吞噬作用的双重靶向。
目的：探讨毛兰素对人结直肠癌细胞（CRC）肿瘤生长和免疫反应的影响。
方法：通过CCK8和集落形成试验确定毛兰素对肿瘤生长的影响。Western印迹用于评估相关蛋白的表达水平，qRT-PCR用于评估相关基因的mRNA水平。通过双荧光素酶报告基因测定法测定β-连环蛋白的转录活性。细胞热位移测定用于量化药物-靶标相互作用。通过流式细胞术评估细胞表面CD47。通过染色质免疫沉淀测定评估CD47启动子上H3K27乙酰标记的富集。吞噬作用测定用于确定巨噬细胞的吞噬活性。在异种移植模型上研究了毛兰素的体内作用。
结果：我们发现毛兰素显着降低了 SW480 和 HCT116 细胞的细胞存活率、集落形成、诱导细胞周期停滞并导致细胞凋亡。机制分析表明，毛兰素抑制β-连环蛋白的核转位和转录活性，这可能是毛兰素-β-连环蛋白相互作用的结果。此外，下游基因表达，如 c-Myc 和 cyclin D1，降低。更有趣的是，毛兰素通过调节 CD47 启动子上 H3K27 乙酰标记的富集来降低 CD47 的表达。因此，巨噬细胞介导的吞噬作用增加。我们的体内实验进一步证实了毛兰素对肿瘤生长的抑制作用。
结论：总之，毛兰素可以抑制结直肠癌细胞的生长并促进吞噬作用，这表明毛兰素可以作为结直肠癌患者的潜在治疗策略。
关键词：毛兰素，结直肠癌，β-连环蛋白，CD47，巨噬细胞
更新日期：2020-08-12
Methods: The effect of erianin on tumor growth was determined by CCK8 and colony formation assay. Western blotting was used to evaluate the expression levels of relevant proteins and qRT-PCR was used to evaluate the mRNA level of the relevant gene. The transcriptional activity of β-catenin was determined by dual-luciferase reporter assay. Cellular thermal shift assay was used to quantify drug–target interactions. The cell surface CD47 was assessed by flow cytometry. The enrichment of H3K27 acetyl marks on CD47 promoter was evaluated by chromatin immunoprecipitation assay. Phagocytosis assay was used to determine the phagocytic activity of macrophage. In vivo role of erianin was studied on xenograft models.
Results: We found that erianin significantly decreased cell survival, colony formation, induced cell cycle arrest, and led to cell apoptosis in SW480 and HCT116 cells. Mechanism analysis demonstrated that erianin inhibited the nuclear translocation and transcriptional activity of β-catenin, which might result from erianin-β-catenin interaction. In addition, the downstream gene expressions, such as c-Myc and cyclin D1, was decreased. More interestingly, erianin decreased the expression of CD47 by regulating H3K27 acetyl marks enrichment on CD47 promoter. Consequently, macrophage-mediated phagocytosis was increased. Our in vivo experiments further confirmed the inhibitory effect of erianin on tumor growth.
Conclusion: In summary, erianin could inhibit CRC cells growth and promoted phagocytosis, which suggested erianin as a potential therapeutic strategy for CRC patients.
Keywords: erianin, colorectal cancer, β-catenin, CD47, macrophage
中文翻译：
Erianin 对人类结直肠癌的细胞生长和吞噬作用的双重靶向。
目的：探讨毛兰素对人结直肠癌细胞（CRC）肿瘤生长和免疫反应的影响。
方法：通过CCK8和集落形成试验确定毛兰素对肿瘤生长的影响。Western印迹用于评估相关蛋白的表达水平，qRT-PCR用于评估相关基因的mRNA水平。通过双荧光素酶报告基因测定法测定β-连环蛋白的转录活性。细胞热位移测定用于量化药物-靶标相互作用。通过流式细胞术评估细胞表面CD47。通过染色质免疫沉淀测定评估CD47启动子上H3K27乙酰标记的富集。吞噬作用测定用于确定巨噬细胞的吞噬活性。在异种移植模型上研究了毛兰素的体内作用。
结果：我们发现毛兰素显着降低了 SW480 和 HCT116 细胞的细胞存活率、集落形成、诱导细胞周期停滞并导致细胞凋亡。机制分析表明，毛兰素抑制β-连环蛋白的核转位和转录活性，这可能是毛兰素-β-连环蛋白相互作用的结果。此外，下游基因表达，如 c-Myc 和 cyclin D1，降低。更有趣的是，毛兰素通过调节 CD47 启动子上 H3K27 乙酰标记的富集来降低 CD47 的表达。因此，巨噬细胞介导的吞噬作用增加。我们的体内实验进一步证实了毛兰素对肿瘤生长的抑制作用。
结论：总之，毛兰素可以抑制结直肠癌细胞的生长并促进吞噬作用，这表明毛兰素可以作为结直肠癌患者的潜在治疗策略。
关键词：毛兰素，结直肠癌，β-连环蛋白，CD47，巨噬细胞
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