Cellular signaling crosstalk between Wnt signaling and gap junctions inbenzo[a]pyrene toxicity
- Authors
- Won, Dong-Hoon; Hwang, Da-Bin; Shin, Yoo-Sub; Kim, Shin-Young; Kim, Changuk; Hong, In-Sun; Kang, Byeong-Cheol; Che, Jeong-Hwan; Yun, Jun-Won
- Issue Date
- Feb-2023
- Publisher
- SPRINGER
- Keywords
- Benzo[a]pyrene; Gap junction; Connexin 43; Wnt; beta-catenin; Toxicity
- Citation
- CELL BIOLOGY AND TOXICOLOGY, v.39, no.1, pp.165 - 182
- Journal Title
- CELL BIOLOGY AND TOXICOLOGY
- Volume
- 39
- Number
- 1
- Start Page
- 165
- End Page
- 182
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/87465
- DOI
- 10.1007/s10565-021-09630-z
- ISSN
- 0742-2091
- Abstract
- Gap junctional intercellular communication (GJIC) is considered a key biological mechanism to maintain homeostasis in cell differentiation and growth. In addition, as another major signaling pathway associated with cell proliferation and differentiation, Wnt/beta-catenin signaling appears to trigger several cellular responses against injury. The purpose of the present study was to investigate the effects of a known toxic agent, benzo[a]pyrene (BaP), on the regulation and interaction between GJIC and Wnt/beta-catenin signaling. BaP treatment resulted in GJIC inhibition and decreases the major GJIC protein connexin 43 (Cx43) in WB-F344 rat liver epithelial cells. We also found BaP-mediated downregulation of Wnt/beta-catenin signaling related to the PI3K-Akt pathway. To identify the relationship between GJIC and Wnt/beta-catenin signaling, we treated WB-F344 cells with the Wnt agonist CHIR99021 and found that it inhibited GJIC while causing a significant reduction in Cx43 expression at both the mRNA and protein levels, through the repression of promoter activity. This Wnt agonist-mediated GJIC inhibition was confirmed using a small interfering RNA directed against the Wnt antagonist Dact2, indicating that Wnt/beta-catenin signaling negatively regulates GJIC. Despite the inverse correlation between Wnt/beta-catenin signaling and Cx43 promoter activation as indicated by downregulation of beta-catenin nuclear translocation and upregulation of Cx43 promoter activation involving HNF3 beta, BaP treatment decreased the Cx43 protein expression, which was associated with protein degradation, possibly through protein kinase C activation. In conclusion, our results revealed the mechanism of BaP-induced inhibition of GJIC and Wnt/beta-catenin signaling. More importantly, linking Wnt/beta-catenin signaling to Cx protein expression will have profound implications in understanding the relationships among different major signaling pathways associated with cell proliferation and differentiation in toxicity.
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