title: Subcytotoxic mercury chloride inhibits gap junction intercellular communication by a redox- and phosphorylation-mediated mechanism.
abstract: Gap junctions play a central role in coordinating intercellular signal-transduction pathways to control tissue homeostasis. Deregulation of gap junctional intercellular communication is a common phenotype of cancer cells and supports its involvement in the carcinogenesis process. Many carcinogens, like environmental heavy-metal chemical pollutants, are known to activate various signal transduction mechanisms and modulate GJIC. They act as tumor promoters on preexisting "initiated" cells, rather than as genotoxic initiators, albeit their mode of action is often unknown. In this study we investigated the effect of Hg(II) (HgCl(2)) on GJIC in cultured human keratinocytes. It is shown that subcytotoxic concentrations of HgCl(2) as low as 10 nM cause inhibition of the GJIC, assessed by dye transfer assay, despite enhanced expression of connexins. In addition, HgCl(2)-treated keratinocytes exhibited a decrease of free thiols and accumulation of mitochondria-derived reactive oxygen species, albeit no effect on the respiratory chain activity was observed. Treatment of HgCl(2)-exposed keratinocytes with the PKC inhibitor calphostin C and with all-trans retinoic acid resulted in rescue of the mitochondrial ROS overproduction and full recovery of the GJIC. Similar results were obtained with the PKA activator db-cAMP. Overall, the presented results support a cross-talk between the altered intracellular redox tone and PKA- and PKC-mediated signaling in HgCl(2)-challenged keratinocytes. These events, although not cytotoxic, lead to inhibition of GJIC and possibly to carcinogenic priming.
authors.affiliation: Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
authors.forename: Annamaria
authors.initials: A
authors.lastname: D'Aprile
authors.forename: Rosella
authors.initials: R
authors.lastname: Scrima
authors.forename: Luigi
authors.initials: L
authors.lastname: Ambrosi
authors.forename: Roberto
authors.initials: R
authors.lastname: Zefferino
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
mesh_terms: D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003603:Cytotoxins / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008627:Mercuric Chloride / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D003603:Cytotoxins; D005456:Fluorescent Dyes; D007546:Isoquinolines; D017382:Reactive Oxygen Species; D008627:Mercuric Chloride; D014212:Tretinoin; C017475:lucifer yellow; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D005978:Glutathione; D019803:Glutathione Disulfide