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

Abstract

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.

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells

“…In this regard, our results corroborate several studies showing luteolin's potential in combined therapy. Various studies have shown that luteolin combined therapy decreased proliferation, apoptosis and autophagy; drugs used include kaempherol in lung adenocarcinoma and 5-fluorouracil in hepatocellular carcinoma [58][59][60].…”

<p>Delivery luteolin with folacin-modified nanoparticle for glioma therapy</p>

“…By regulating intricate signal transduction pathways, luteolin presents multiple antineoplastic effects, such as antitumor cell proliferation, anticarcinogen effects, blocking cell cycle progression, inducing tumor cells apoptosis,inhibiting the infiltration and metastasis of tumor and the growth of new vessels, etc. [11][12][13][14][15] It is rather difficult for luteolin to reach the target region of glioma because luteolin is sparingly soluble in water and thus its bioavailability is fairly low orally, and it is usually very difficult to go through blood-brain barrier (BBB) or blood tumor barrier (BTB). Even though luteolin penetrates BBB and reaches the target region of glioma, it is hard to attain sustaining, effective drug concentration to inhibit or kill tumor cells.…”

Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression

“…Total RNA was isolated from the cells using TRI reagent (Molecular Research Center, Cincinnati, OH, USA). Reverse transcription and quantitative real-time PCR were performed using specific primers against human CLDN2 and the threshold cycle for each PCR product was calculated as described previously [20].…”