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

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 GSK3β by abrogation of Akt-mediated GSK3β phosphorylation at Ser9. The activated GSK3β 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.

• Authors: 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
• Journal: Carcinogenesis (Carcinogenesis) Vol. 36 Issue 10 Pg. 1223-34 (Oct 2015) ISSN: 1460-2180 [Electronic] England
• PMID: 26243309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Benzodioxoles
• Lignans
• Multiprotein Complexes
• aschantin
• Epidermal Growth Factor
• MTOR protein, human
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Benzodioxoles (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects, genetics)
• Epidermal Growth Factor (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, genetics)
• Glycogen Synthase Kinase 3 beta
• Humans
• Lignans (administration & dosage)
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Multiprotein Complexes (antagonists & inhibitors)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics)