title: 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.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Cheol-Jung
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea, College of Pharmacy, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Jang
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gun, ChungBuk 363-883, Republic of Korea.
authors.forename: Hyung Won
authors.initials: HW
authors.lastname: Ryu
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Kyung-Il
authors.initials: KI
authors.lastname: Choi
authors.affiliation: The Hormel Institute, University of Minnesota, 801, 16th AVE, NE, Austin, MN 55912, USA and.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gun, ChungBuk 363-883, Republic of Korea.
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea, yongyeon@catholic.ac.kr surh@plaza.snu.ac.kr.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.affiliation: College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea, yongyeon@catholic.ac.kr.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017705:Lignans / Q000008:administration & dosage*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D052117:Benzodioxoles; D017705:Lignans; D046912:Multiprotein Complexes; C550309:aschantin; D004815:Epidermal Growth Factor; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3