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Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response. | LitMetric

AI Article Synopsis

  • Polycyclic aromatic hydrocarbons (PAHs) and dioxin-like compounds (DLCs) activate the aryl hydrocarbon receptor (AHR), which is important for understanding disease mechanisms and developing treatments, but different compounds can trigger different AHR responses.
  • The epidermal growth factor receptor (EGFR) plays a significant role in how AHR ligands affect cellular responses, especially in human epithelial cells, where exposure to certain compounds leads to altered EGFR activity.
  • Research indicates that compounds like benzo[a]pyrene (B[a]P) induce unique processes, such as the activation of aldo-keto reductase 1C3, while DLCs can inhibit EGFR activation, highlighting the complexity

Article Abstract

Polycyclic aromatic hydrocarbons (PAHs), dioxin-like compounds (DLCs) and structurally-related environmental pollutants may contribute to the pathogenesis of various diseases and disorders, primarily by activating the aryl hydrocarbon receptor (AHR) and modulating downstream cellular responses. Accordingly, AHR is considered an attractive molecular target for preventive and therapeutic measures. However, toxicological risk assessment of AHR-modulating compounds as well as drug development is complicated by the fact that different ligands elicit remarkably different AHR responses. By elucidating the differential effects of PAHs and DLCs on aldo-keto reductase 1C3 expression and associated prostaglandin D metabolism, we here provide evidence that the epidermal growth factor receptor (EGFR) substantially shapes AHR ligand-induced responses in human epithelial cells, i.e. primary and immortalized keratinocytes and breast cancer cells. Exposure to benzo[a]pyrene (B[a]P) and dioxin-like polychlorinated biphenyl (PCB) 126 resulted in a rapid c-Src-mediated phosphorylation of EGFR. Moreover, both AHR agonists stimulated protein kinase C activity and enhanced the ectodomain shedding of cell surface-bound EGFR ligands. However, only upon B[a]P treatment, this process resulted in an auto-/paracrine activation of EGFR and a subsequent induction of aldo-keto reductase 1C3 and 11-ketoreduction of prostaglandin D. Receptor binding and internalization assays, docking analyses and mutational amino acid exchange confirmed that DLCs, but not B[a]P, bind to the EGFR extracellular domain, thereby blocking EGFR activation by growth factors. Finally, nanopore long-read RNA-seq revealed hundreds of genes, whose expression is regulated by B[a]P, but not by PCB126, and sensitive towards pharmacological EGFR inhibition. Our data provide novel mechanistic insights into the ligand response of AHR signaling and identify EGFR as an effector of environmental chemicals.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8852774PMC
http://dx.doi.org/10.1016/j.envint.2021.106989DOI Listing

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