Cocoa polyphenols attenuate hydrogen peroxide-induced inhibition of gap-junction intercellular communication by blocking phosphorylation of connexin 43 via the MEK/ERK signaling pathway.
Cocoa, a good source of dietary antioxidative polyphenols, exhibited anticarcinogenic activity in animal models, but the molecular mechanisms of the chemopreventive potential of cocoa remain unclear. Inhibition of gap-junction intercellular communication (GJIC) is strongly related to tumorigenesis. Cocoa polyphenol extracts (CPE) dose dependently attenuated hydrogen peroxide (H(2)O(2))-induced inhibition of GJIC in rat liver epithelial (RLE) cells. CPE inhibited the H(2)O(2)-induced phosphorylation and internalization of connexin 43, which is a regulating protein of GJIC in RLE cells. The H(2)O(2)-induced accumulation of reactive oxygen species and activation of extracellular signal-regulated kinase were inhibited by CPE treatment. However, CPE did not block H(2)O(2)-induced phosphorylation of p38 mitogen-activated protein kinase. An ex vivo kinase assay demonstrated that CPE inhibited the H(2)O(2)-induced mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1 activity in RLE cell lysates. Ex vivo pull-down assay data revealed that CPE directly bound with MEK1 to inhibit MEK1 activity. These results indicate that CPE protects against the H(2)O(2)-induced inhibition of GJIC through antioxidant activity and direct inhibition of MEK activity, which may contribute to its chemopreventive potential.
Lee
Dong Eun
DE
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
Kang
Nam Joo
NJ
Lee
Kyung Mi
KM
Lee
Bo Kyung
BK
Kim
Jong Hun
JH
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
D000818:Animals; D002099:Cacao / Q000737:chemistry*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D051381:Rats
D018031:Connexin 43; D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D006861:Hydrogen Peroxide