title: Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation.
abstract: Mitogen-activated protein kinases play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of cell proliferation by suppression of the G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer cells and NIH3T3 cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting cell proliferation and transformation by targeting ERK1 and ERK2.
authors.affiliation: Integrated Research Institute of Pharmaceutical Sciences, 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.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Hyung Won
authors.initials: HW
authors.lastname: Ryu
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Hyeong-Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Sei-Ryang
authors.initials: SR
authors.lastname: Oh
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D017705:Lignans; C094148:magnolin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins