Celastrol acts as a new histone deacetylase inhibitor to inhibit colorectal cancer cell growth via regulating macrophage polarity
Celastrol acts as a new histone deacetylase inhibitor to inhibit colorectal cancer cell growth via regulating macrophage polarity
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DOI：
10.1002/cbin.11952
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发表时间：
2022-11
影响因子：
3.9
通讯作者：
Shuren Wang;Guanghui Hu;Lechuang Chen;Kai Ma;Chenfei Hu;Hongxia Zhu;N. Xu;Changchun Zhou;Mei Liu
中科院分区：
文献类型：
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作者：
Shuren Wang;Guanghui Hu;Lechuang Chen;Kai Ma;Chenfei Hu;Hongxia Zhu;N. Xu;Changchun Zhou;Mei Liu
结直肠癌的发生、发展与肿瘤微环境尤其是炎症反应密切相关。组蛋白去乙酰化酶（HDAC）抑制剂已被报道作为免疫系统的表观遗传调节剂来治疗癌症和炎性疾病，并且我们的结果表明雷公藤红素可以作为新的HDAC抑制剂。考虑到巨噬细胞是肿瘤微环境的重要成员，我们进一步发现雷公藤红素可以影响巨噬细胞的极化，从而抑制结直肠癌细胞的生长。特别地，我们使用HCT 116和SW 480细胞的上清液体外诱导Ana-1细胞，并选择自发性结直肠癌模型APC min/+小鼠作为动物模型进行体内验证。结果表明，雷公藤红素可通过影响体内外结直肠肿瘤微环境，逆转巨噬细胞从M2向M1的极化。此外，通过生物信息学分析，我们发现雷公藤红素可能通过MAPK信号通路对巨噬细胞产生作用。综上所述，我们的研究结果证实了雷公藤红素是一种新的HDAC抑制剂，并提示雷公藤红素可以调节巨噬细胞极化，从而抑制结直肠癌的生长，这可能为结直肠癌的治疗提供一些新的策略。
The tumorigenesis and progression of colorectal cancer are closely related to the tumor microenvironment, especially inflammatory response. Inhibitors of histone deacetylase (HDAC) have been reported as epigenetic regulators of the immune system to treat cancer and inflammatory diseases and our results demonstrated that Celastrol could act as a new HDAC inhibitor. Considering macrophages as important members of the tumor microenvironment, we further found that Celastrol could influence the polarization of macrophages to inhibit colorectal cancer cell growth. Specially, we used the supernatant of HCT116 and SW480 cells to induce Ana‐1 cells in vitro and chose the spontaneous colorectal cancer model APCmin/+ mice as an animal model to validate in vivo. The results indicated that Celastrol could reverse the polarization of macrophages from M2 to M1 through impacting the colorectal tumor microenvironment both in vitro and in vivo. Furthermore, using bioinformatics analysis, we found that Celastrol might mechanistically polarize the macrophages through MAPK signaling pathway. In conclusion, our findings identified that Celastrol as a new HDAC inhibitor and suggested that Celastrol could modulate macrophage polarization, thus inhibiting colorectal cancer growth, which may provide some novel therapeutic strategies for colorectal cancer.