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

Abstract:

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.

journal_name

Onco Targets Ther

journal_title

OncoTargets and therapy

authors

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

doi

10.2147/OTT.S187315

subject

Has Abstract

pub_date

2018-12-11 00:00:00

pages

8977-8985

issn

1178-6930

pii

ott-11-8977

journal_volume

11

pub_type

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