This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Simon, C. Articles by Boyd, D. Search for Related Content PubMed PubMed Citation Articles by Simon, C. Articles by Boyd, D.

Effect of PD 098059, a Specific Inhibitor of Mitogen-activated Protein Kinase Kinase, on Urokinase Expression and in Vitro Invasion¹

Departments of Head and Neck Surgery and Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 [C. S., J. J., D. B.], and Institute for Molecular Medicine, Irvine California 92619-2470 [G. L. N.]

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 , 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.

¹ This work was supported by NIH Grants R01 DE10845 and CA51539 (D. B.), a grant from the National Foundation for Cancer Research (G. L. N.), and a fellowship (Si 634/1-1) from the Deutsche Forschungsgemeinschaft (C.S.).

² To whom requests for reprints should be addressed, at Department of Tumor Biology, M. D. Anderson Cancer Center, Box 108, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8953; Fax: (713) 794-0209.

Received 8/26/96. Accepted 10/17/96.

This article has been cited by other articles:

				B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]

				S. Benvenuti, A. Sartore-Bianchi, F. Di Nicolantonio, C. Zanon, M. Moroni, S. Veronese, S. Siena, and A. Bardelli Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti-Epidermal Growth Factor Receptor Antibody Therapies Cancer Res., March 15, 2007; 67(6): 2643 - 2648. [Abstract] [Full Text] [PDF]

				H. Huynh, K. C. Soo, P. K.H. Chow, and E. Tran Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma Mol. Cancer Ther., January 1, 2007; 6(1): 138 - 146. [Abstract] [Full Text] [PDF]

				M.-S. Kim, E.-J. Lee, H.-R. C. Kim, and A. Moon p38 Kinase Is a Key Signaling Molecule for H-Ras-induced Cell Motility and Invasive Phenotype in Human Breast Epithelial Cells Cancer Res., September 1, 2003; 63(17): 5454 - 5461. [Abstract] [Full Text] [PDF]

				Z. Ma, D. J. Webb, M. Jo, and S. L. Gonias Endogenously produced urokinase-type plasminogen activator is a major determinant of the basal level of activated ERK/MAP kinase and prevents apoptosis in MDA-MB-231 breast cancer cells J. Cell Sci., March 11, 2002; 114(18): 3387 - 3396. [Abstract] [Full Text] [PDF]

				M. Hidalgo and S. G. Eckhardt Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy J Natl Cancer Inst, February 7, 2001; 93(3): 178 - 193. [Abstract] [Full Text] [PDF]

				C. P. Webb, C. D. Hose, S. Koochekpour, M. Jeffers, M. Oskarsson, E. Sausville, A. Monks, and G. F. Vande Woude The Geldanamycins Are Potent Inhibitors of the Hepatocyte Growth Factor/Scatter Factor-Met-Urokinase Plasminogen Activator-Plasmin Proteolytic Network Cancer Res., January 1, 2000; 60(2): 342 - 349. [Abstract] [Full Text]

				D. Webb, D. Nguyen, and S. Gonias Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion J. Cell Sci., January 1, 2000; 113(1): 123 - 134. [Abstract] [PDF]

				M. Janulis, S. Silberman, A. Ambegaokar, J. S. Gutkind, and R. M. Schultz Role of Mitogen-activated Protein Kinases and c-Jun/AP-1 trans-Activating Activity in the Regulation of Protease mRNAs and the Malignant Phenotype in NIH 3T3 Fibroblasts J. Biol. Chem., January 8, 1999; 274(2): 801 - 813. [Abstract] [Full Text] [PDF]

				M. Jeffers, M. Fiscella, C. P. Webb, M. Anver, S. Koochekpour, and G. F. Vande Woude The mutationally activated Met receptor mediates motility and metastasis PNAS, November 24, 1998; 95(24): 14417 - 14422. [Abstract] [Full Text] [PDF]

				C. P. Webb, L. Van Aelst, M. H. Wigler, and G. F. Vande Woude Signaling pathways in Ras-mediated tumorigenicity and metastasis PNAS, July 21, 1998; 95(15): 8773 - 8778. [Abstract] [Full Text] [PDF]

				M. F. Favata, K. Y. Horiuchi, E. J. Manos, A. J. Daulerio, D. A. Stradley, W. S. Feeser, D. E. Van Dyk, W. J. Pitts, R. A. Earl, F. Hobbs, et al. Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase J. Biol. Chem., July 17, 1998; 273(29): 18623 - 18632. [Abstract] [Full Text] [PDF]