Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases

Honami Yonezawa; Akari Ikeda; Ryo Takahashi; Haruka Endo; Yasuyo Sugawara; Mikako Goto; Mirute Kanno; Sosuke Ogawa; Karin Nakamura; Haruki Ujiie; Masato Iwatsuki; Tomoyasu Hirose; Toshiaki Sunazuka; Yoshimasa Uehara; Naoyuki Nishiya

doi:10.1016/j.isci.2022.103912

Ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases

iScience. 2022 Mar 7;25(3):103912. doi: 10.1016/j.isci.2022.103912. eCollection 2022 Mar 18.

Authors

Affiliations

¹ Division of Integrated Information for Pharmaceutical Sciences, Department of Clinical Pharmacy, Iwate Medical University School of Pharmacy, Shiwa-gun, Yahaba-cho, Iwate 028-3694, Japan.
² Ōmura Satoshi Memorial Institute and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Minato-ku 108-8641, Japan.

Abstract

Ivermectin (IVM), an avermectin-derivative anthelmintic, specifically binds to glutamate-gated chloride ion channels (GluCls), causing paralysis in invertebrates. IVM also exhibits other biological activities such as Wnt/β-catenin pathway inhibition in vertebrates that do not possess GluCls. This study showed that affinity purification using immobilized IVM B1a isolated TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases (PIKKs), as a specific IVM B1a-binding protein. TELO2 knockdown reduced cytoplasmic β-catenin and the transcriptional activation of β-catenin/TCF. IVM B1a bound to TELO2 through the C-terminal α-helix, in which mutations conferred IVM resistance. IVM reduced the TELO2 and PIKK protein levels and the AKT and S6 kinase phosphorylation levels. The inhibition of mTOR kinase reduced the cytoplasmic β-catenin level. Therefore, IVM binds to TELO2, inhibiting PIKKs and reducing the cytoplasmic β-catenin level. In conclusion, our data indicate TELO2 as a druggable target for human diseases involving abnormalities of the Wnt/β-catenin pathway and PIKKs, including mTOR.

Keywords: Biochemistry; Molecular biology; Small molecule.