Resveratrol counteracts gallic acid-induced down-regulation of gap-junction intercellular communication

Since reactive oxygen species (ROS) play a key role in carcinogenesis, many studies have focused on the chemopreventive activities of naturally occurring antioxidants. However, the possibility that different antioxidants in food exert opposing effects on carcinogenesis has not been adequately investigated. Gap-junction intercellular communication (GJIC), which is strongly related to carcinogenesis (particularly the tumor promotion stage), may be a suitable model for investigating the tumor-promoting and antitumor-promoting effects of phytochemicals. The present study investigated the possible combined effects of resveratrol and gallic acid (GA), which are major antioxidants in red wine, on GJIC in WB-F344 rat liver epithelial (RLE) cells. GA at 100 μM, but not resveratrol, inhibited GJIC and generated hydrogen peroxide. The GA-induced inhibition of GJIC was recovered by resveratrol, but only partially recovered by catalase. Resveratrol did not attenuate GA-induced generation of hydrogen peroxide, but it did block GA-induced phosphorylation of connexin 43 (Cx43), a key modulator of GJIC. Furthermore, resveratrol down-regulated GA-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, one of the critical regulators of Cx43. However, catalase partially blocked the GA-induced phosphorylation of Cx43 and ERK1/2. Collectively, these findings suggest that the combined effects of red wine phenolic phytochemicals on GJIC and antioxidants differ in ROS-mediated carcinogenesis depending on their dosages and structures.