Interactions between the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and protein kinase C (PKC) signaling pathways are governed in cell and tissue-specific manners, albeit the physiological significance of which is unclear. This research sought to define the effects of TCDD on the PKC pathway using a mouse ovarian surface epithelial cancer cell line (ID8). Phorbol-12-myristate-13-acetate (PMA) potentiated (1nM) TCDD-induced 7-ethoxyresorufin-O-deethylase (EROD) activity after 24h of treatment, and pre-treatment with (1μM) of either a general PKC inhibitor (BisI) or PKCδ-specific inhibitor (Rotterlin) abolished the potentiation indicating that activation of PKC enhances TCDD signal transduction. Western blot analysis revealed that unstimulated ID8 cells express PKCα, β, ε, τ, λ and RACK1. PKCγ, η, θ and DGKθ were not detected. TCDD (1nM) increased PKCδ protein approximately eight-fold after 24h of treatment and this effect was dose-dependent (0.1-100nM); other PKC isoforms and related signaling proteins tested were unaffected by TCDD treatment. Immunofluorescent microscopy revealed that TCDD (1nM) promoted the subcellular redistribution of PKCδ, from the cytoplasm and the nucleus to the perinuclear area after 2h of treatment, however, after 24h of treatment PKCδ was observed in nuclear structures that resembled nucleoli. TCDD (1nM) also increased total PKC and PKCδ-specific kinase activities in biphasic time-responsive manners. Total PKC and PKCδ-specific activities increased after 1-2h of treatment. Then TCDD increased the total PKC activity again after 12h of treatment, whereas, PKCδ-specific activity resurged at 24h and remained elevated at 48h after treatment. The results indicate that TCDD preferentially induces PKCδ protein expression and phosphotransferase activity, and its membrane translocation, indicating a potential intracellular role for PKCδ as an effector molecule for TCDD-mediated biological events in this ovarian cancer cell line. © 2003 Elsevier Ireland Ltd. All rights reserved.
Williams, S. R., Son, D. S., & Terranova, P. F. (2004). Protein kinase C δ is activated in mouse ovarian surface epithelial cancer cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology, 195(1), 1–17. https://doi.org/10.1016/j.tox.2003.08.005