title: Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF-289 by activation of nuclear factor kappaB1 and mitogen-activated protein kinase pathways.
abstract: Extracellular nucleotides have a profound role in the regulation of the proliferation of diseased tissue. We studied how extracellular nucleotides regulate the proliferation of LXF-289 cells, the adenocarcinoma-derived cell line from human lung bronchial tumor. ATP and ADP strongly inhibited LXF-289 cell proliferation. The nucleotide potency profile was ATP = ADP = ATPgammaS > > UTP, UDP, whereas alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, 2',3'-O-(4-benzoylbenzoyl)-ATP, AMP and UMP were inactive. The nucleotide potency profile and the total blockade of the ATP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 clearly show that P2Y receptors, but not P2X receptors, control LXF-289 cell proliferation. Treatment of proliferating LXF-289 cells with 100 microm ATP or ADP induced significant reduction of cell number and massive accumulation of cells in the S phase. Arrest in S phase is also indicated by the enhancement of the antiproliferative effect of ATP by coapplication of the cytostatic drugs cisplatin, paclitaxel and etoposide. Inhibition of LXF-289 cell proliferation by ATP was completely reversed by inhibitors of extracellular signal related kinase-activating kinase/extracellular signal related kinase 1/2 (PD98059, U0126), p38 mitogen-activated protein kinase (SB203508), phosphatidylinositol-3-kinase (wortmannin), and nuclear factor kappaB1 (SN50). Western blot analysis revealed transient activation of p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, and nuclear factor kappaB1 and possibly new formation of p50 from its precursor p105. ATP-induced attenuation of LXF-289 cell proliferation was accompanied by transient translocation of p50 nuclear factor kappaB1 and extracellular signal-related kinase 1/2 to the nucleus in a similar time period. In summary, inhibition of LXF-289 cell proliferation is mediated via P2Y receptors by activation of multiple mitogen-activated protein kinase pathways and nuclear factor kappaB1, arresting the cells in the S phase.
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität, Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schäfer
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Fariba
authors.initials: F
authors.lastname: Sedehizade
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D052002:NF-kappa B p50 Subunit; D018048:Receptors, Purinergic P2; C022571:adenosine 5'-O-(3-thiotriphosphate); D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020928:Mitogen-Activated Protein Kinases