Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells
Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells
复制标题
雷公藤红醇抑制埃兹蛋白介导的肝癌细胞迁移
DOI：
10.1038/s41598-020-68238-1
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发表时间：
2020-07-09
影响因子：
4.6
通讯作者：
Ding, Xia
中科院分区：
文献类型：
--
作者：
Du, Shihao;Song, Xiaoyu;Ding, Xia
肝细胞癌的进展涉及促进癌症侵袭和转移的多种遗传和表观遗传改变。我们最近的研究表明，ezrin的过度磷酸化促进体内肝内转移和体外细胞迁移。南蛇藤酚是一种传统中药的天然产物，用于治疗肝癌。然而，雷公藤红素治疗的作用机制尚不清楚。在这里，我们表明ROCK 2是雷公藤红素的一个新靶点，抑制ROCK 2可以抑制引起的埃兹蛋白激活和肝癌细胞迁移。使用细胞单层伤口愈合，我们进行了基于表型的天然产物筛选，并发现雷公藤红素抑制细胞迁移的功效。通过雷公藤红素亲和下拉法鉴定其作用靶点为ROCK 2。我们的分子对接分析表明雷公藤红素与ROCK 2激酶的活性位点结合。从机制上讲，雷公藤红素抑制ROCK 2介导的埃兹蛋白在Thr 567处的磷酸化，这利用了肝癌细胞的迁移。我们的研究结果表明，靶向ROCK 2-ezrin信号传导是一个潜在的治疗利基为雷公藤红素为基础的干预肝癌的癌症进展。
Progression of hepatocellular carcinoma involves multiple genetic and epigenetic alterations that promote cancer invasion and metastasis. Our recent study revealed that hyperphosphorylation of ezrin promotes intrahepatic metastasis in vivo and cell migration in vitro. Celastrol is a natural product from traditional Chinese medicine which has been used in treating liver cancer. However, the mechanism of action underlying celastrol treatment was less clear. Here we show that ROCK2 is a novel target of celastrol and inhibition of ROCK2 suppresses elicited ezrin activation and liver cancer cell migration. Using cell monolayer wound healing, we carried out a phenotype-based screen of natural products and discovered the efficacy of celastrol in inhibiting cell migration. The molecular target of celastrol was identified as ROCK2 using celastrol affinity pull-down assay. Our molecular docking analyses indicated celastrol binds to the active site of ROCK2 kinase. Mechanistically, celastrol inhibits the ROCK2-mediated phosphorylation of ezrin at Thr567 which harnesses liver cancer cell migration. Our findings suggest that targeting ROCK2-ezrin signaling is a potential therapeutic niche for celastrol-based intervention of cancer progression in hepatocellular carcinoma.