Celastrol induces ubiquitin-dependent degradation of mTOR in breast cancer cells

• Published in: OncoTargets and therapy Vol. 11; pp. 8977 - 8985
• Main Authors: Li, Xiaoli, Zhu, Guangbei, Yao, Xintong, Wang, Ning, Hu, Ronghui, Kong, Qingxin, Zhou, Duanfang, Long, Liangyuan, Cai, Jiali, Zhou, Weiying
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2018; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Asian medicine; Autoimmune diseases; Breast cancer; Cancer cells; Cancer research; Cell cycle; Cell growth; EDTA; Everolimus; Experiments; Growth factors; Heat shock proteins; Kinases; Laboratories; Metabolism; Original Research; Pharmacy; Phosphorylation; Prostate; Proteins; Traditional Chinese medicine; Trends; Tumors; Ubiquitin; Xenografts; United States > US; China; Hsp90; celastrol; mTOR; Cdc37; Chinese medicine; ubiquitin
• ISSN: 1178-6930; 1178-6930
• DOI: 10.2147/OTT.S187315

Celastrol is a major active component of the thunder god vine ( ) used in traditional Chinese medicine to treat chronic inflammatory and autoimmune diseases. Celastrol inhibits PI3K-Akt-mTOR signaling, which is frequently dysregulated in tumors and critical for tumor-cell proliferation and survival, but the underlying mechanisms are still not fully understood. In the present study, we investigated detailed mechanisms of celastrol inhibition of mTOR signaling in breast cancer cells. First, we evaluated the effect of celastrol on breast cancer-cell growth using MTT assays. Second, we examined the effects of celastrol on mTOR phosphorylation and expression using Western blot. Furthermore, we investigated the cause of mTOR downregulation by celastrol using immunoprecipitation assays. In addition, we evaluated the effect of celastrol on an MDA-MB231 cell-derived xenograft model. Celastrol suppressed breast cancer cell growth in vitro and in vivo. Celastrol inhibited mTOR phosphorylation and induced mTOR ubiquitination, resulting in its proteasomal degradation. Mechanistically, we found that mTOR is a client of Hsp90-Cdc37 chaperone complex, and celastrol disrupts mTOR interaction with chaperone Hsp90 while promoting mTOR association with cochaperone Cdc37. Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.