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Aschantin targeting on the kinase domain of mammalian target of rapamycin suppresses epidermal growth factor-induced neoplastic cell transformation

Cited 11 time in Web of Science Cited 11 time in Scopus
Authors
Lee, Cheol-Jung; Jang, Jeong-Hoon; Lee, Ji-Young; Lee, Mee-Hyun; Li, Yan; Ryu, Hyung Won; Choi, Kyung-Il; Dong, Zigang; Lee, Hye Suk; Oh, Sei-Ryang; Surh, Young-Joon; Cho, Yong-Yeon
Issue Date
2015-10
Citation
Carcinogenesis, Vol.36 No.10, pp.1223-1234
Abstract
Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, forms two different complexes, complex 1 and 2, and plays a key role in the regulation of Akt signaling-mediated cell proliferation and transformation. This study reveals aschantin, a natural compound abundantly found in Magnolia flos, as a novel mTOR kinase inhibitor. Aschantin directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not PI3K and PDK1. Aschantin inhibited epidermal growth factor (EGF)-induced full activation of Akt by phosphorylation at Ser473/Thr308, resulting in inhibition of the mTORC2/Akt and Akt/mTORC1/p70S6K signaling pathways and activation of GSK3 beta by abrogation of Akt-mediated GSK3 beta phosphorylation at Ser9. The activated GSK3 beta inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through the ubiquitination-mediated proteasomal degradation pathway. Notably, aschantin treatment decreased c-Jun stability through inhibition of the mTORC2-Akt signaling pathway, which suppressed EGF-induced anchorage-independent cell transformation in non-malignant JB6 Cl41 and HaCaT cells and colony growth of LNCaP and MIAPaCa-2 cancer cells in soft agar. Altogether, the results show that aschantin targets mTOR kinase and destabilizes c-Jun, which implicate aschantin as a potential chemopreventive or therapeutic agent.
ISSN
0143-3334
URI
https://hdl.handle.net/10371/172625
DOI
https://doi.org/10.1093/carcin/bgv113
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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