Tumor promoting properties of a cigarette smoke prevalent polycyclic aromatic hydrocarbon as indicated by the inhibition of gap junctional intercellular communication via phosphatidylcholine-specific phospholipase C

Cancer Sci. 2008 Apr;99(4):696-705. doi: 10.1111/j.1349-7006.2008.00752.x.


Inhibition of gap junctional intercellular communication (GJIC) and the activation of intracellular mitogenic pathways are common hallmarks of epithelial derived cancer cells. We previously determined that the 1-methyl and not the 2-methyl isomer of anthracene, which are prominent cigarette smoke components, activated extracellular receptor kinase, and inhibited GJIC in WB-F344 rat liver epithelial cells. Using these same cells, we show that an immediate upstream response to 1-methylanthracene was a rapid (<1 min) release of arachidonic acid. Inhibition of phosphatidylcholine-specific phospholipase C prevented the inhibition of GJIC by 1-methylanthracene. In contrast, inhibition of phosphatidylinositol specific phospholipase C, phospholipase A(2), diacylglycerol lipase, phospholipase D, protein kinase C, and tyrosine protein kinases had no effect on 1-methylanthracene-induced inhibition of GJIC. Inhibition of protein kinase A also prevented inhibition of GJIC by 1-methylanthracene. Direct measurement of phosphatidylcholine-specific phospholipase C and sphingomyelinase indicated that only phosphatidylcholine-specific phospholipase C was activated in response to 1-methylanthracene, while 2-methylanthracene had no effect. 1-methylanthracene also activated p38-mitogen activated protein kinase; however, like extracellular kinase, its activation was not involved in 1-methylanthracene-induced regulation of GJIC, and this activation was independent of phosphatidylcholine-specific phospholipase C. Although mitogen activated protein kinases were activated, Western blot analyzes indicated no change in connexin43 phosphorylation status. Our results indicate that phosphatidylcholine-specific phospholipase C is an important enzyme in the induction of a tumorigenic phenotype, namely the inhibition of GJIC; whereas mitogen activated protein kinases triggered in response to 1-methylanthracene, were not involved in the deregulation of GJIC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / chemistry
  • Anthracenes / toxicity*
  • Carcinogens, Environmental / toxicity*
  • Cell Communication / drug effects
  • Cell Line
  • Connexin 43 / analysis
  • Connexin 43 / metabolism
  • Connexins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gap Junctions / chemistry
  • Gap Junctions / drug effects*
  • Gap Junctions / metabolism
  • Neoplasms / chemically induced
  • Neoplasms / enzymology
  • Nicotiana / toxicity
  • Phosphorylation
  • Rats
  • Smoke
  • Sphingomyelin Phosphodiesterase / analysis
  • Sphingomyelin Phosphodiesterase / metabolism
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Anthracenes
  • Carcinogens, Environmental
  • Connexin 43
  • Connexins
  • Enzyme Inhibitors
  • Smoke
  • 1-methylanthracene
  • 2-methylanthracene
  • p38 Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • Sphingomyelin Phosphodiesterase
  • phosphatidylcholine-specific phospholipase C