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

Na Hui Kim1, Minji Kwon1, Jiwoo Jung1, Hyo Byeong Chae2, Jiwoo Lee2, Yeo-Jun Yoon3, In Seok Moon3, Ho K. Lee4, Wan Namkung4, Konstantina M. Stankovic5, Se A. Lee6, Jong Dae Lee6, Sin-Aye Park1,2
1 Department of ICT Environmental Health System, Graduate School, Soonchunhyang University, Asan-si 31538, Republic of Korea
2 Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan-si 31538, Republic of Korea
3 Department of Otorhinolaryngology, Yonsei University, College of Medicine, Seoul 03722, Republic of Korea
4 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Yeonsu-gu, Incheon 21983, Republic of Korea
5 Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
6 Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea
Correspondence to: Jong Dae Lee:, Sin-Aye Park:,
DOI: 10.1038/s41401-022-00908-4
Received: 22 November 2021
Accepted: 2 April 2022
Advance online: 27 April 2022


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.

Keywords: celastrol; natural products; tumor growth; vestibular schwannoma; β-catenin degradation; Wnt/β-catenin

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