Subcytotoxic mercury chloride inhibits gap junction intercellular communication by a redox-and phosphorylation-mediated mechanism

Claudia Piccoli, Annamaria D'Aprile, Rosella Scrima, Luigi Ambrosi, Roberto Zefferino, Nazzareno Capitanio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)916-927
Number of pages12
JournalFree Radical Biology and Medicine
Volume52
Issue number5
DOIs
Publication statusPublished - Mar 1 2012

Keywords

  • connexin 43
  • gap junction intercellular communication
  • mercury toxicity
  • mitochondria
  • reactive oxygen species
  • redox signaling

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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