title: Benzo[a]pyrene-7,8-diol-9,10-epoxide inhibits gap junction intercellular communication via phosphorylation of tumor progression locus 2 in WB-F344 rat liver epithelial cells.
abstract: Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), a major metabolite of benzo[a]pyrene, has been reported to function as a human carcinogen. However, the molecular mechanism of how B[a]PDE regulates signaling pathways during tumor promotion remains unclear. In this study, we investigated the effects of B[a]PDE on the regulation of gap junction intercellular communication (GJIC), one of the major carcinogenic processes, and its main regulatory signaling pathways using WB-F344 rat liver epithelial (WB-F344 RLE) cells. Treatment of benzo[a]pyrene or B[a]PDE resulted in GJIC inhibition, and B[a]PDE was more active at lower concentrations than benzo[a]pyrene in the suppression of GJIC. This suggests that B[a]PDE is a stronger GJIC inhibitor. B[a]PDE at 1 µM reversibly inhibited GJIC in WB-F344 RLE cells, which was attributable to hyperphosphorylation of connexin43 (Cx43) via phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). We found that B[a]PDE induced phosphorylation of tumor progression locus 2 (Tpl2), a direct upstream regulator of MEK. Tpl2 inhibitor recovered B[a]PDE-induced GJIC inhibition and attenuated B[a]PDE-induced MEK/ERK phosphorylation in WB-F344 RLE cells. Collectively, our results suggest that B[a]PDE suppresses GJIC by activating Tpl2 and subsequently the MEK/ERK pathway and Cx43 phosphorylation in WB-F344 RLE cells. These results outline the potential importance of Tpl2 as a novel therapeutic target for B[a]PDE-induced GJIC inhibition during cancer promotion.
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul, 143-701, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, 443-270, Republic of Korea.
authors.forename: Bo Kyung
authors.initials: BK
authors.lastname: Lee
authors.forename: Min-Yu
authors.initials: MY
authors.lastname: Chung
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction
chemical_list: D002273:Carcinogens; D018031:Connexin 43; D011518:Proto-Oncogene Proteins; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C080356:Map3k8 protein, rat
keywords: benzo[a]pyrene-7,8-diol-9,10-epoxide; connexin43; gap junction intercellular communication; tumor progression locus 2