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Am J Physiol Lung Cell Mol Physiol (April 11, 2003). doi:10.1152/ajplung.00447.2002
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Submitted on December 30, 2002
Accepted on March 27, 2003

ATP and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells

Rainer Schafer1, Fariba Sedehizade1, Tobias Welte2, and Georg Reiser1*

1 Institut fuer Neurobiochemie, Otto-von-Guericke-Universitaet, Magdeburg, Germany
2 Klinik fuer Kardiologie, Angiologie und Pneumologie, Otto-von-Guericke-Universitaet, Magdeburg, Germany

* To whom correspondence should be addressed. E-mail: georg.reiser{at}medizin.uni-magdeburg.de.

The involvement of P2Y receptors (P2Y-R) which are activated by extracellular nucleotides in proliferative regulation of human lung epithelial cells is still unclear. Here we show that extracellular ATP and UTP stimulate BrdU incorporation into epithelial cell lines. The nucleotide efficacy profile (ATP = ADP > UDP >= UTP >> adenosine >= 2-MeSADP with {alpha},{beta}-MeATP, Bz-ATP, AMP, UMP and ATP{alpha}S inactive) and PCR analysis indicate involvement of P2Y2-R and P2Y6-R. The signal transduction pathway, which via P2Y2-R transmits the proliferative activity of ATP or UTP in A549 cells, downstream of phospholipase C depends on CaMKII, and NF-{kappa}B, yet not on PKC. Signaling does not involve MAP kinases Erk 1/2, the PI-3 kinase pathway or Src kinases. Thus, nucleotides regulate proliferation of human lung epithelial cells by a novel pathway. The stimulatory effect of UTP, but not that of ATP, in A549 cells is attenuated by preincubation with IL-1{beta} and IL-6, but not TNF-{alpha}. This indicates an important role of pyrimidine-activated P2Y-R in the inflammatory response of lung epithelia. ATP antagonizes the antiproliferative effect of anti-cancer drugs paclitaxel and etoposide, whereas it enhances the activity of cisplatin about 4-fold. Thus, pathways activated by extracellular nucleotides differentially control proliferation of lung epithelial tumor cells.




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