Systematic identification of Celastrol-binding proteins reveals that Shoc2 is inhibited by Celastrol

Author:

Xiao-pei Huang1,Ji-kuai Chen1,Xue Wei1,Dong Yi-Fan1,Yan Lang1,Xiao-fang Zhang1,Ya-min Pan2,Wen-jun Chang3,Jiang-bo Zhu1

Affiliation:

1. Department of Health Toxicology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, P.R. China

2. The First Department of Endoscopy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China

3. Department of Environmental Hygiene, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, P.R. China

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer. Celastrol exhibits anti-tumor activities in a variety of cancers. However, the effect of Celastrol on human CRC and the underlying mechanisms still need to be elucidated. The present study aimed to use in vitro and in vivo methods to clarify the anti-tumor effect of Celastrol and use protein microarrays to explore its mechanisms. We demonstrated that Celastrol effectively inhibited SW480 CRC cell proliferation. Two weeks of Celastrol gavage significantly inhibited the growth of xenografts in nude mice. A total of 69 candidate proteins were identified in the protein microarray experiment, including the most highly enriched protein Shoc2, which is a scaffold protein that modulates cell motility and metastasis through the ERK pathway. Celastrol significantly inhibited ERK1/2 phosphorylation in cell lines and xenograft tumors. Down-regulation of Shoc2 expression using Shoc2 siRNA also inhibited ERK1/2 phosphorylation. Furthermore, down-regulation of Shoc2 expression also significantly inhibited proliferation, colony formation, and migration functions of tumor cells. In addition, the LD0 of Celastrol by gavage is equal or more than 80 mg/kg in C57 male mice. In summary, we unraveled the anti-CRC function of Celastrol and confirmed for the first time that it inhibited the ERK1/2 pathway through binding to Shoc2.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry,Biophysics

Reference36 articles.

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