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Open AccessArticle

Kaempherol and Luteolin Decrease Claudin-2 Expression Mediated by Inhibition of STAT3 in Lung Adenocarcinoma A549 Cells

From the Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
Institute for Chemical Research, Kyoto University, Kyoto 611-0011, Japan
Nagaragawa Research Center, API Co., Ltd., Gifu 502-0071, Japan
Author to whom correspondence should be addressed.
Nutrients 2017, 9(6), 597;
Received: 8 April 2017 / Revised: 3 June 2017 / Accepted: 10 June 2017 / Published: 13 June 2017
(This article belongs to the Special Issue Effects of Polyphenol-Rich Foods on Human Health)
Claudin-2 is highly expressed in human lung adenocarcinoma tissues and may be a novel target for cancer chemotherapy because knockdown of claudin-2 decreases cell proliferation. We found that flavonoids including kaempferol, chrysin, and luteolin concentration-dependently decrease claudin-2 expression in lung adenocarcinoma A549 cells. Claudin-2 expression is up-regulated by mitogen-activated protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK)/c-Fos and phosphoinositide 3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) pathways, but these activities were not inhibited by kaempferol, chrysin, and luteolin. Promoter deletion assay using luciferase reporter vector showed that kaempferol and luteolin inhibit the function of transcriptional factor that binds to the region between −395 and −144 of claudin-2 promoter. The decrease in promoter activity was suppressed by mutation in signal transducers and activators of transcription (STAT)-binding site, which is located between −395 and −144. The phosphorylation level of STAT3 was not decreased, but the binding of STAT3 on the promoter region is suppressed by kaempferol and luteolin in chromatin immunoprecipitation assay. The inhibition of cell proliferation caused by kaempferol and luteolin was partially recovered by ectopic claudin-2 expression. Taken together, kaempferol and luteolin decreased claudin-2 expression and proliferation in A549 cells mediated by the inhibition of binding of STAT3 on the promoter region of claudin-2. The intake of foods and nutrients rich in these flavonoids may prevent lung adenocarcinoma development. View Full-Text
Keywords: lung adenocarcinoma; claudin-2; kaempferol; chrysin; STAT3 lung adenocarcinoma; claudin-2; kaempferol; chrysin; STAT3
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Sonoki, H.; Tanimae, A.; Endo, S.; Matsunaga, T.; Furuta, T.; Ichihara, K.; Ikari, A. Kaempherol and Luteolin Decrease Claudin-2 Expression Mediated by Inhibition of STAT3 in Lung Adenocarcinoma A549 Cells. Nutrients 2017, 9, 597.

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