Phorbol ester-modulation of estrogenic genomic effects triggered by the environmental contaminant benzanthracene.
Aryl hydrocarbon receptor-dependent genomic effects of environmental polycyclic aromatic hydrocarbons (PAHs) have been shown to be modulated by non-genomic protein kinase C (PKC)-related pathways. The present study was designed to determine whether PKC activation may also impair estrogenic genomic response triggered by PAHs. Treatment by the PKC activator phorbol 12-myristate 13-acetate (PMA) was found to markedly and differentially impair the up-regulation of estrogenic markers triggered by the estrogenic PAH benzanthracene (BZA) in cultured human mammary cells; BZA-mediated mRNA up-regulation of pS2 and amphiregulin was thus increased, whereas that of progesterone receptor and CXCL12 was repressed. BZA/PMA cotreatment however failed to alter BZA-mediated increase of activity of a luciferase gene reporter construct driven by an estrogen response element, thus discarding any global effect of PMA toward BZA-triggered estrogen receptor activation. Various chemicals inhibiting PKCs or extracellular signal-regulated kinase (ERK) as well as the knock-down of PKCδ expression counteracted the PMA-mediated increase of pS2 mRNA up-regulation triggered by BZA, demonstrating that it was dependent on PKCs, including PKCδ isoform, and ERKs. This non-genomic modulation of estrogenic effects of PAHs by PKC activation may have to be considered when considering the deleterious effects of these environmental contaminants towards the endocrine system.
Institut de Recherche en Santé, Environnement et Travail, UMR INSERM U1085, Université de Rennes 1, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, F-35043 Rennes, France.
Elise
E
Kolasa
Patrick
P
Balaguer
Noémie
N
Houlbert
Olivier
O
Fardel
D066258:Amphiregulin; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D066255:EGF Family of Proteins; D004785:Environmental Pollutants / Q000633:toxicity*; D004967:Estrogens / Q000633:toxicity*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics
C587848:AREG protein, human; D066258:Amphiregulin; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D066255:EGF Family of Proteins; D004785:Environmental Pollutants; D004967:Estrogens; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate