2. Academic Validation
  3. Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells

Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells

  • Sci Rep. 2020 Jul 9;10(1):11273. doi: 10.1038/s41598-020-68238-1.
Shihao Du  # 1 2,  Xiaoyu Song  # 3,  Yuan Li  # 2,  Yalei Cao  # 1,  Fuhao Chu 1,  Olanrewaju Ayodeji Durojaye 3,  Zeqi Su 1,  Xiaoguang Shi 2,  Jing Wang 2,  Juan Cheng 2,  Tangshun Wang 2,  Xiang Gao 2,  Yan Chen 2,  Wuzhekai Zeng 3,  Fengsong Wang 4,  DongMei Wang 3,  Xing Liu 3,  Xia Ding 5 6
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 2 Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
  • 3 MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China.
  • 4 School of Life Science, Anhui Medical University, Hefei, 230032, China.
  • 5 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. dingx@bucm.edu.cn.
  • 6 Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China. dingx@bucm.edu.cn.
  • # Contributed equally.
PMID: 32647287 DOI: 10.1038/s41598-020-68238-1
Abstract

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.

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