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bDepartment of Food Science and Technology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, South Korea cCollege of Pharmacy, Seoul National University, Seoul 151-742, South Korea dCollege of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
aAddress for correspondence: Hyong Joo Lee, Department of Food Science and Technology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, South Korea. Voice: 82-2-880-4853; fax: 82-2-873-5095. e-mail: leehyjo{at}snu.ac.kr
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 µM 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
 B (NF-B) activation. We also found that CAPE significantly inhibited H-ras-induced NF-B 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-B.
Key Words: H-ras • cyclooxygenase-2 • gap junction intercellular communication • nuclear factor B • caffeic acid phenethyl ester • rat liver epithelial cells
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