title: 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.
abstract: 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.
authors: Department of Pediatrics & Human Development, Michigan State University, East Lansing, MI 48824, USA. upham@msu.edu
authors: Brad L
authors: BL
authors: Upham
authors: Ludek
authors: L
authors: Bláha
authors: Pavel
authors: P
authors: Babica
authors: Joon-Suk
authors: JS
authors: Park
authors: Iva
authors: I
authors: Sovadinova
authors: Charles
authors: C
authors: Pudrith
authors: Alisa M
authors: AM
authors: Rummel
authors: Liliane M
authors: LM
authors: Weis
authors: Kimie
authors: K
authors: Sai
authors: Patti K
authors: PK
authors: Tithof
authors: Miodrag
authors: M
authors: Guzvić
authors: Jan
authors: J
authors: Vondrácek
authors: Miroslav
authors: M
authors: Machala
authors: James E
authors: JE
authors: Trosko
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000032:analysis / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000139:chemically induced / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D012906:Smoke; D013108:Sphingomyelin Phosphodiesterase / Q000032:analysis / Q000378:metabolism; D014026:Nicotiana / Q000633:toxicity; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002274:Carcinogens, Environmental; D018031:Connexin 43; D017630:Connexins; D004791:Enzyme Inhibitors; D012906:Smoke; C051246:1-methylanthracene; C051247:2-methylanthracene; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D013108:Sphingomyelin Phosphodiesterase; C105598:phosphatidylcholine-specific phospholipase C