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

1 Institut für Neurobiochemie and 2 Klinik für Kardiologie, Angiologie, und Pneumologie, Medizinische Fakultät, Otto-von-Guericke-Universität, 39120 Magdeburg, Germany Submitted 30 December 2002 ; accepted in final form 27 March 2003 The involvement of P2Y receptors, which are activated by extracellular nucleotides, in proliferative regulation of human lung epithelial cells is unclear. Here we show that extracellular ATP and UTP stimulate bromodeoxyuridine (BrdU) incorporation into epithelial cell lines. The nucleotide efficacy profile [ATP = ADP > UDP UTP > adenosine 2-methylthioadenosine-5'-diphosphate, with , -methylene adenosine 5'-triphosphate, 2',3'- O -(4-benzoylbenzoyl)adenosine 5'-triphosphate, AMP, UMP, and ATP S inactive] and PCR analysis indicate involvement of P2Y 2 and P2Y 6 receptors. The signal transduction pathway, which, via the P2Y 2 receptor, transmits the proliferative activity of ATP or UTP in A549 cells downstream of phospholipase C, depends on Ca 2 + /calmodulin-dependent protein kinase II and nuclear factor- B, but not on protein kinase C. Signaling does not involve the mitogen-activated protein kinases extracellular signal-regulated kinases-1 and -2, the phosphatidylinositol 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 ATP, in A549 cells is attenuated by preincubation with interleukin-1 and interleukin-6, but not tumor ncerosis factor- . This indicates an important role for the pyrimidine-activated P2Y receptor in the inflammatory response of lung epithelia. ATP antagonizes the antiproliferative effect of the anticancer drugs paclitaxel and etoposide, whereas it enhances the activity of cisplatin about fourfold. Thus pathways activated by extracellular nucleotides differentially control proliferation of lung epithelial tumor cells. purinergic receptors; cancer; cytokines; extracellular nucleotides Address for reprint requests and other correspondence: G. Reiser, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Str. 44, 39120 Magdeburg, Germany (E-mail: georg.reiser{at}medizin.uni-magdeburg.de ).