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Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF‐289 by activation of nuclear factor κB1 and mitogen‐activated protein kinase pathways
Author(s) -
Schäfer Rainer,
Hartig Roland,
Sedehizade Fariba,
Welte Tobias,
Reiser Georg
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05384.x
Subject(s) - wortmannin , kinase , protein kinase a , biology , cyclin dependent kinase 2 , microbiology and biotechnology , mitogen activated protein kinase kinase , cell growth , biochemistry , phosphatidylinositol
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 = ATPγS > > UTP, UDP, whereas α,β‐methylene‐ATP, β,γ‐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 µ m 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 κB1 (SN50). Western blot analysis revealed transient activation of p38 mitogen‐activated protein kinase, extracellular signal‐related kinase 1/2, and nuclear factor κB1 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 κB1 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 κB1, arresting the cells in the S phase.