Abstract 1249: ERK1/2 targeting with magnolin as a chemopreventive agent

Mitogen activated protein kinases (MAPKs) play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/ERKs/RSK2 signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC 50 values of 87 nM and 16.5 nM by competing with ATP in an active pocket, respectively. Further, we demonstrated that magnolin inhibited EGF-induced p90RSKs phopshorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, resulted in inhibition of cell proliferation by suppression of G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases, and Akts did not involved magnolin-mediated inhibitory signaling. Magnolin targeting on 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. Citation Format: Cheol-Jung Lee, Mee-Hyun Lee, Ji-Young Lee, Ji Hong Song, Yong-Yeon Cho. ERK1/2 targeting with magnolin as a chemopreventive agent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2014-1249