Naringin attenuates EGF-induced MUC5AC secretion in A549 cells by suppressing the cooperative activities of MAPKs-AP-1 and IKKs-IκB-NF-κB signaling pathways

• Published in: European journal of pharmacology Vol. 690; no. 1-3; pp. 207 - 213
• Main Authors: Nie, Yi-chu, Wu, Hao, Li, Pei-bo, Xie, Li-ming, Luo, Yu-long, Shen, Jian-gang, Su, Wei-wei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.09.2012
• Subjects: Activator protein-1; azithromycin; binding sites; Cell Line, Tumor; Cell Survival - drug effects; epidermal growth factor; Epidermal Growth Factor - antagonists & inhibitors; Epidermal Growth Factor - pharmacology; epidermal growth factor receptors; Epithelium growth factor; Epithelium growth factor receptor; Flavanones - pharmacology; Gene Expression Regulation - drug effects; Humans; I-kappa B Kinase - metabolism; MAP Kinase Signaling System - drug effects; messenger RNA; mitogen-activated protein kinase; MUC5AC; Mucin 5AC - secretion; mucins; naringenin; Naringin; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nuclear factor kappa B; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; phosphorylation; Protein Kinase Inhibitors - pharmacology; secretion; signal transduction; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism; transcription factor NF-kappa B; Activator protein-1; Naringin; Epithelium growth factor receptor; MUC5AC; Epithelium growth factor; Nuclear factor kappa B
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.06.040

Naringenin, the aglycone of naringin, has been reported to attenuate MUC5AC secretion by inhibiting activity of nuclear factor kappa B (NF-κB) via EGFR-PI3K-Akt/ERK MAPKinase signaling pathways. However, previous studies demonstrated that the MUC5AC promoter was located in two different regions: an activator protein-1 (AP-1) binding site and a NF-κB binding site. The current study comprehensively determined the involvement of MAPKs/AP-1 and IKKs/IκB/NF-κB in epidermal growth factor (EGF)-induced A549 cells, and sought to ascertain the signaling pathways of naringin imparted in suppression of EGF-induced MUC5AC secretion. The results showed that naringin of 100μM not only significantly decreased EGF-induced overexpressions of both MUC5AC mucin and mRNA in A549 cells, but also suppressed the phosphorylation of EGF receptor, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK), as well as nucleus NF-κB p65 and AP-1. Moreover, any of three MAPKs inhibitors (PD98059, SB203580, and SP600125) significantly inhibited EGF-induced MUC5AC secretion. And as compared to MG132, the inhibitor κB (IκB) phosphorylation inhibitor of SN50 was more effective in reducing EGF-induced MUC5AC secretion because of suppression of nucleus AP-1. Meanwhile, as compared to naringin, both SP600125 and azithromycin were less effective in suppressing EGF-induced secretion of MUC5AC because of the unchanged nucleus NF-κB p65. These results indicated that naringin attenuates EGF-induced MUC5AC secretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. [Display omitted]