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

Cheol Jung Lee, Jeong Hoon Jang, Ji Young Lee, Mee Hyun Lee, Yan Li, Hyung Won Ryu, Kyung Il Choi, Zigang Dong, Hye Suk Lee, Sei Ryang Oh, Young Joon Surh, Yong Yeon Cho

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 GSK3ß by abrogation of Akt-mediated GSK3ß phosphorylation at Ser9. The activated GSK3ß inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through the ubiquitinationmediated 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.

Original languageEnglish (US)
Article numberbgv107
Pages (from-to)1223-1234
Number of pages12
JournalCarcinogenesis
Volume36
Issue number10
DOIs
StatePublished - Aug 16 2015

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