Galanin, neurotensin, and phorbol esters rapidly stimulate activation of mitogen-activated protein kinase in small cell lung cancer cells.
Addition of phorbol 12,13-dibutyrate (PDB) to H 69, H 345, and H 510 small cell lung cancer (SCLC) cells led to a rapid concentration- and time-dependent increase in p42mapk activity. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one], a selective inhibitor of mitogen activated protein kinase (MAPK) kinase 1, prevented activation of p42mapk by PDB in SCLC cells. PDB also stimulated the activation of p90rsk, a major downstream target of p42mapk. The effect of PDB on both p42mapk and p90rsk activation could be prevented by down-regulation of protein kinase C (PKC) by prolonged pretreatment with 800 nM PDB or treatment of SCLC cells with the PKC inhibitor bisindolylmaleimide (GF 109203X), demonstrating the involvement of phorbol ester-sensitive PKCs in the signaling pathway leading to p42mapk activation. Various neuropeptides, such as bradykinin, vasopressin, bombesin, neurotensin, and galanin, which promote clonal growth in SCLC cells, also induced activation of p42mapk in these cells. In particular, galanin and neurotensin stimulated p42mapk activation in SCLC cells by a pathway that was dependent on the activity of PKC. Furthermore, galanin-stimulated clonal growth of SCLC cells in semisolid medium could be prevented by the PKC inhibitor GF 109203X and by PD 098059. Thus, our results suggest that activation of p42mapk plays an important role in neuropeptide-induced growth of SCLC.
Seufferlein
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Imperial Cancer Research Fund, London, United Kingdom.
Rozengurt
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D001920:Bradykinin / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000201:enzymology*; D015536:Down-Regulation; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D019004:Galanin / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1; D009363:Neoplasm Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D009496:Neurotensin / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D002273:Carcinogens; D005419:Flavonoids; D009363:Neoplasm Proteins; D009479:Neuropeptides; D010566:Virulence Factors, Bordetella; D015240:Phorbol 12,13-Dibutyrate; D009496:Neurotensin; D019004:Galanin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D001920:Bradykinin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one