Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation

Cheol Jung Lee, Hye Suk Lee, Hyung Won Ryu, Mee Hyun Lee, Ji Young Lee, Yan Li, Zigang Dong, Hyeong Kyu Lee, Sei Ryang Oh, Yong Yeon Cho

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 RasG12V-harboring A549 human lung cancer cells and NIH3T3 cells stably expressing RasG12V 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.

Original languageEnglish (US)
Article numberbgt306
Pages (from-to)432-441
Number of pages10
JournalCarcinogenesis
Volume35
Issue number2
DOIs
StatePublished - Feb 2014

Bibliographical note

Funding Information:
Research Fund, The Catholic University of Korea (M-2011-B0002-00025); Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2000961); Korea Research Institute of Bioscience and Biotechnology Initiative Program (KGM1221312).

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

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