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

Authors Li X, Zhu G, Yao X, Wang N, Hu R, Kong Q, Zhou D, Long L, Cai J, Zhou W

Received 12 September 2018

Accepted for publication 24 October 2018

Published 11 December 2018 Volume 2018:11 Pages 8977—8985

DOI https://doi.org/10.2147/OTT.S187315

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Takuya Aoki


Xiaoli Li,1–3,* Guangbei Zhu,4,* Xintong Yao,2,3 Ning Wang,5 Ronghui Hu,6 Qingxin Kong,7 Duanfang Zhou,1–3 Liangyuan Long,1–3 Jiali Cai,4 Weiying Zhou1–3

1Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, P.R. China; 2Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, P.R. China; 3Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing 400016, P.R. China; 4Dapartment of Biophamaceutics, School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P.R. China; 5First Affiliated Hospital’s Central Laboratory, Army Medical University, Chongqing 400038, P.R. China; 6Department of Radiology, Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, P.R. China; 7Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Jiangsu 223003, P.R. China

*These authors contributed equally to this work

Background: Celastrol is a major active component of the thunder god vine (Tripterygium wilfordii) 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.
Methods: 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.
Results: 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.
Conclusion: Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.

Keywords: celastrol, mTOR, Hsp90, Cdc37, ubiquitin, Chinese medicine

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