title: Inhibition of cyclooxygenase-2 expression and restoration of gap junction intercellular communication in H-ras-transformed rat liver epithelial cells by caffeic acid phenethyl ester.
abstract: One of the most frequent defects in human cancers is the uncontrolled activation of the ras signaling pathways. Increased expression of cyclooxygenase-2 (COX-2) and inhibition of gap junction intercellular communication (GJIC) have been frequently observed in several forms of human malignancies. The present study investigated the effects of caffeic acid phenethyl ester (CAPE), a chemopreventive phytochemical derived from honey propolis, on COX-2 expression and GJIC in Harvey-ras-transformed WB-F344 rat liver epithelial cells (H-ras WB cells). H-ras induced COX-2 expression in WB-F344 rat liver epithelial cells (WB cells). H-ras WB cells also exhibited complete inhibition of GJIC and predominant unphosphorylation of connexin 43 (Cx43), a major protein modulating GJIC. CAPE significantly inhibited the constitutive expression of COX-2 and restored the disrupted GJIC through the phosphorylation of Cx43 at a concentration of 12.5 microM in H-ras WB cells. Although the molecular basis for the cancer chemopreventive activity of CAPE is not completely understood, several studies suggest that CAPE is a potent and specific inhibitor of the transcription factor nuclear factor kappaB (NF-kappaB) activation. We also found that CAPE significantly inhibited H-ras-induced NF-kappaB DNA-binding activity without affecting the activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which are major intracellular molecules involved in the Ras signaling pathways. In conclusion, CAPE may exert cancer chemopreventive effects through the inhibition of COX-2 expression and the restoration of disrupted GJIC induced by H-ras, possibly by targeting NF-kappaB.
authors.affiliation: Department of Food Science and Technology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Chun
authors.forename: Jeong-Sang
authors.initials: JS
authors.lastname: Lee
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology*; D002450:Cell Communication; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015342:DNA Probes; D024202:Electrophoretic Mobility Shift Assay; D017629:Gap Junctions / Q000378:metabolism*; D011905:Genes, ras; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats
chemical_list: D002109:Caffeic Acids; D017931:DNA Primers; D015342:DNA Probes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol