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Celastrol suppresses the growth of vestibular schwannoma in mice by promoting the degradation of β-catenin

Authors
 Na Hui Kim  ;  Minji Kwon  ;  Jiwoo Jung  ;  Hyo Byeong Chae  ;  Jiwoo Lee  ;  Yeo-Jun Yoon  ;  In Seok Moon  ;  Ho K Lee  ;  Wan Namkung  ;  Konstantina M Stankovic  ;  Se A Lee  ;  Jong Dae Lee  ;  Sin-Aye Park 
Citation
 ACTA PHARMACOLOGICA SINICA, Vol.43(11) : 2993-3001, 2022-11 
Journal Title
ACTA PHARMACOLOGICA SINICA
ISSN
 1671-4083 
Issue Date
2022-11
MeSH
Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Mice ; Mice, Nude ; Neuroma, Acoustic* / drug therapy ; Neuroma, Acoustic* / metabolism ; Neuroma, Acoustic* / pathology ; Pentacyclic Triterpenes / pharmacology ; Wnt Signaling Pathway ; beta Catenin* / metabolism
Keywords
Wnt/β-catenin ; celastrol ; natural products ; tumor growth ; vestibular schwannoma ; β-catenin degradation
Abstract
Vestibular schwannoma (VS), one of characteristic tumors of neurofibromatosis type 2 (NF2), is an intracranial tumor that arises from Schwann cells of the vestibular nerve. VS results in hearing loss, tinnitus, dizziness, and even death, but there are currently no FDA-approved drugs for treatment. In this study, we established a high-throughput screening to discover effective compounds that could inhibit the viability of VS cells. Among 1019 natural products from the Korea Chemical Bank screened, we found that celastrol, a pentacyclic triterpene derived from a Tripterygium Wilfordi plant, exerted potent inhibitory effect on the viability of VS cells with an IC50 value of 0.5 µM. Celastrol (0.5, 1 µM) dose-dependently inhibited the proliferation of primary VS cells derived from VS patients. Celastrol also inhibited the growth, and induced apoptosis of two other VS cell lines (HEI-193 and SC4). Aberrant activation of Wnt/β-catenin signaling has been found in VS isolated from clinically defined NF2 patients. In HEI-193 and SC4 cells, we demonstrated that celastrol (0.1, 0.5 μM) dose-dependently inhibited TOPFlash reporter activity and protein expression of β-catenin, but not mRNA level of β-catenin. Furthermore, celastrol accelerated the degradation of β-catenin by promoting the formation of the β-catenin destruction complex. In nude mice bearing VS cell line SC4 allografts, administration of celastrol (1.25 mg · kg-1 · d-1, i.p. once every 3 days for 2 weeks) significantly suppressed the tumor growth without showing toxicity. Collectively, this study demonstrates that celastrol can inhibit Wnt/β-catenin signaling by promoting the degradation of β-catenin, consequently inhibiting the growth of VS.
Full Text
https://www.nature.com/articles/s41401-022-00908-4
DOI
10.1038/s41401-022-00908-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Moon, In Seok(문인석) ORCID logo https://orcid.org/0000-0002-3951-5074
Yoon, Y J(윤여준)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/192289
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