Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells.
Tangeretin (5,6,7,8,4'-pentamethoxyflavone) is a polymethoxylated flavonoid concentrated in the peel of citrus fruits. Recent studies have shown that tangeretin exhibits anti-proliferative, anti-invasive, anti-metastatic, and antioxidant activities. However, the anti-inflammatory properties of tangeretin are unclear. In this study, we examine the effects of tangeretin and its structure-related compound, nobiletin, on the expression of cyclooxygenases-2 (COX-2) in human lung epithelial carcinoma cells, A549, and human non-small cell lung carcinoma cells, H1299. Tangeretin exerts a much better inhibitory activity than nobiletin against IL-1beta-induced production of COX-2 in A549 cells, and it effectively represses the constitutively expressed COX-2 in H1299. RT-PCR was used to investigate the transcriptional inhibition of COX-2 by tangeretin. COX-2 mRNA was rapidly induced by IL-1beta in 3h and markedly suppressed by tangeretin. IL-1beta-induced the activation of ERK, p38 MAPK, JNK, and AKT in A549 cells. COX-2 expression in response to IL-1beta was attenuated by pretreatment with SB203580, SP600125, and LY294002, but not with PD98059, suggesting the involvement of p38 MAPK, JNK, and PI3K in this response. Pretreatment of cells with tangeretin inhibited IL-1beta-induced p38 MAPK, JNK, and AKT phosphorylation and the downstream activation of NF-kappaB. These results may reveal that the tangeretin inhibition of IL-1beta-induced COX-2 expression in A549 cells is, at least in part, mediated through suppression of NF-kappaB transcription factor as well as through suppression of the signaling proteins of p38 MAPK, JNK, and PI3K, but not of ERK.
Chen
Kuan-Hung
KH
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 10018, Taiwan.
Weng
Meng-Shih
MS
Lin
Jen-Kun
JK
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D017931:DNA Primers; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D047309:Flavones; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D051546:Cyclooxygenase 2; C059006:tangeretin