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

   
@article{APS10719,
	author = {Na Hui Kim and Minji Kwon and Jiwoo Jung and Hyo Byeong Chae and Jiwoo Lee and Yeo-Jun Yoon and In Seok Moon and Ho K. Lee and Wan Namkung and Konstantina M. Stankovic and Se A. Lee and Jong Dae Lee and Sin-Aye Park},
	title = {Celastrol suppresses the growth of vestibular schwannoma in mice by promoting the degradation of β-catenin},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {11},
	year = {2022},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10719}
}