ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells.
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 >or= UTP > adenosine >or= 2-methylthioadenosine-5'-diphosphate, with alpha,beta-methylene adenosine 5'-triphosphate, 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, AMP, UMP, and ATPalphaS inactive] and PCR analysis indicate involvement of P2Y2 and P2Y6 receptors. The signal transduction pathway, which, via the P2Y2 receptor, transmits the proliferative activity of ATP or UTP in A549 cells downstream of phospholipase C, depends on Ca2+/calmodulin-dependent protein kinase II and nuclear factor-kappaB, 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-1beta and interleukin-6, but not tumor necrosis factor-alpha. 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.
Schafer
Rainer
R
Institut für Neurobiochemie, Otto-von-Guericke-Universität, 39120 Magdeburg, Germany.
Sedehizade
Fariba
F
Welte
Tobias
T
Reiser
Georg
G
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D014544:Uridine Triphosphate / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C546385:P2RY2 protein, human; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D012265:Ribonucleotides; C099845:purinoceptor P2Y6; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate