Effect of PD 098059, a specific inhibitor of mitogen-activated protein kinase kinase, on urokinase expression and in vitro invasion.
The elevated expression of the urokinase-type plasminogen activator gene, which is necessary for the invasive phenotype of several types of cancers, is controlled by growth factors such as epidermal growth factor, transforming growth factor a, and fibroblast growth factor which bind to and activate protein tyrosine kinase transmembrane receptors. Since these activated receptors communicate with the nucleus via a signaling pathway in which c-Raf-1, mitogen-activated protein kinase kinase 1 (MEK1), and the extracellular signal-regulated kinases are sequentially activated, we determined the effect of a specific MEK1 inhibitor (PD 098059) on urokinase expression in two squamous cell carcinoma cell lines (UM-SCC-1 and MDA-TU-138) characterized as avid secretors of the plasminogen activator. PD 098059 treatment of either cell line reduced the amount of secreted urokinase in a dose-dependent manner. In contrast, a compound (daidzein) chemically unrelated to PD 098059 had little effect on urokinase secretion. The effect of PD 098059 on urokinase secretion in UM-SCC-1 cells was reversible and correlated with decreased extracellular signal-regulated kinase 1 activity. PD 098059 caused a dose-dependent reduction in the in vitro invasiveness of UM-SCC-1 cells whereas it had little effect on proliferation rates. Transient transfection assays with a chloramphenicol acetyl transferase reporter driven by the urokinase promoter indicated that diminished secretion of the protease was largely a consequence of reduced promoter activity. These findings suggest that interfering with MEK1 may provide a novel means of controlling the invasiveness of tumors in which this signaling cascade is activated by autocrine and/or paracrine growth factors.
Simon
C
C
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Juarez
J
J
Nicolson
G L
GL
Boyd
D
D
D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007529:Isoflavones; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C004742:daidzein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D014568:Urokinase-Type Plasminogen Activator; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one