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.