Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells

• Published in: Scientific reports 2020-07, Vol.10 (1), p.11273-11273, Article 11273
• Main Authors: Du, Shihao, Song, Xiaoyu, Li, Yuan, Cao, Yalei, Chu, Fuhao, Durojaye, Olanrewaju Ayodeji, Su, Zeqi, Shi, Xiaoguang, Wang, Jing, Cheng, Juan, Wang, Tangshun, Gao, Xiang, Chen, Yan, Zeng, Wuzhekai, Wang, Fengsong, Wang, DongMei, Liu, Xing, Ding, Xia
• Format: Article
• Language: English
• Subjects: 631/45; 631/80/84; 631/92; 692/699/67/1504/1610; Biotin - chemistry; Carcinoma, Hepatocellular - metabolism; Catalytic Domain; Cell activation; Cell adhesion & migration; Cell migration; Cell Movement; Cytoskeletal Proteins - chemistry; Disease Progression; Epigenetics; Ezrin; HEK293 Cells; Hep G2 Cells; Hepatocellular carcinoma; Hepatocytes; Herbal medicine; Humanities and Social Sciences; Humans; Kinases; Liver cancer; Liver Neoplasms - metabolism; Medicine, Chinese Traditional; Metastases; Metastasis; Molecular Docking Simulation; multidisciplinary; Natural products; Neoplasm Invasiveness; Neoplasm Metastasis; Phenotypes; Phosphorylation; rho-Associated Kinases - metabolism; Science; Science (multidisciplinary); Traditional Chinese medicine; Triterpenes - pharmacology; Wound Healing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-68238-1

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.