Abstract 2810: Identification of a natural compound as mammalian target of rapamycin kinase inhibitor

Abstract

Abstract The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, plays a critical role in the regulation of Akt signaling-mediated cell proliferation and transformation. Although several synthetic chemical compounds have developed to inhibit mTOR kinase activity, only few publications have been reported on the identification of natural compounds to target the mTOR kinase active pocket. In this study, we found that AME, a natural compound, inhibited cell proliferation by impairment of G1/S cell cycle transition when cells were co-treated with tumor promoters, such as epidermal growth factor. AME directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not with PI3K and PDK1. We further confirmed that AME inhibited phosphorylation of Akt at Ser473, which is a target amino acid of mTOR complex 2 (mTORC2), and Akt-mediated GSK3β phosphorylation at Ser9, which resulted in activation of GSK3β. The activated GSK3β inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through an ubiquitination-mediated proteasomal degradation pathway. Notably, decreased c-Jun stability by AME treatment suppressed EGF-induced neoplastic cell transformation in JB6 Cl41 mouse skin epidermal cells and HaCaT human skin keratinocytes in soft agar assay. Taken together, these results demonstrated that AME might be a natural chemopreventive agent targeting mTOR kinase active pocket. Key words: Natural compound, ATP-competitive mTOR kinase inhibitor, mTORC2/Akt/GSK3 signaling, chemoprevention Citation Format: Jeong-Hoon Jang, Cheol-Jung Lee, Mee-Hyun Lee, Young-Joon Surh, Yong-Yeon Cho. Identification of a natural compound as mammalian target of rapamycin kinase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2810. doi:10.1158/1538-7445.AM2015-2810