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

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 0.5M. Celastrol (0.5, 1M) 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/beta-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 muM) dose-dependently inhibited TOPFlash reporter activity and protein expression of beta-catenin, but not mRNA level of beta-catenin. Furthermore, celastrol accelerated the degradation of beta-catenin by promoting the formation of the beta-catenin destruction complex. In nude mice bearing VS cell line SC4 allografts, administration of celastrol (1.25mg·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/beta-catenin signaling by promoting the degradation of beta-catenin, consequently inhibiting the growth of VS.

View details for DOI 10.1038/s41401-022-00908-4

View details for PubMedID 35478244