Abstract
BackgroundMagnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. The aim of this study is to evaluate the effects of magnolin on cell migration and to further explore the molecular mechanisms involved.MethodsMagnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2+/+ and RSK2−/− MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-κB and Cox-2 promoter luciferase reporter assays. Inhibition of cell migration by magnolin was examined by wound healing and/or Boyden Chamber assays using JB6 Cl41 and A549 human lung cancer cells. The molecular mechanisms involved in cell migration and epithelial-to-mesenchymal transition were determined by zymography, Western blotting, real-time PCR and immunocytofluorescence.ResultsMagnolin inhibited NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Moreover, magnolin abrogated the increase in EGF-induced COX-2 protein levels and wound healing. In human lung cancer cells such as A549 and NCI-H1975, which harbor constitutive active Ras and EGFR mutants, respectively, magnolin suppressed wound healing and cell invasion as seen by a Boyden chamber assay. In addition, it was observed that magnolin inhibited MMP-2 and −9 gene expression and activity. The knockdown or knockout of RSK2 in A549 lung cancer cells or MEFs revealed that magnolin targeting ERKs/RSK2 signaling suppressed epithelial-to-mesenchymal transition by modulating EMT marker proteins such as N-cadherin, E-cadherin, Snail, Vimentin and MMPs.ConclusionsThese results demonstrate that magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1580-7) contains supplementary material, which is available to authorized users.
Highlights
Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions
We found that AP-1 and Nuclear factor-κB (NF-κB) transactivation activities were downregulated by the inhibition of ERK1/2-mediated RSK2 activity [5, 20], suggesting that magnolin may suppress the gene expression of Cox-2, an enzyme that plays an important role in cancer cell proliferation, motility and metastasis [24]
Our previous results have demonstrated that RSK2 induced the proteasomal degradation of IκBα by phosphorylation at Ser32, resulting in activation of NF-κB transactivation activity [20], and magnolin, a natural compound abundantly found in Shin-Yi (Fig. 1a and Additional file 1: Figure S1), inhibited ERK1 and ERK2 [5]
Summary
Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. Methods: Magnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2+/+ and RSK2−/− MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-κB and Cox-2 promoter luciferase reporter assays. Our previous results have demonstrated that the enhanced cAMP-dependent transcription factor 1 (ATF1) activity, caused by the epidermal growth factor (EGF)-mediated Ras/ERKs/RSK2 signaling pathway, induces cell proliferation and transformation [16]. The Ras/ERKs/RSK2 signaling axis may be a key signaling pathway in the regulation of cell proliferation and transformation, and in cancer cell metastasis
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