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Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion
  1. E. C. Koon*,,
  2. P. C. Ma,
  3. R. Salgia§,
  4. W. R. Welch,,
  5. J. G. Christensen,
  6. R. S. Berkowitz*, and
  7. S. C. Mok*,
  1. * Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
  2. Dana-Farber Harvard Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts;
  3. Division of Hematology/Oncology, University Hospitals Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, Ohio;
  4. § Section of Hematology/Oncology, Department of Medicine, University of Chicago, Pritzker School of Medicine, University of Chicago Cancer Research Center, Chicago, Illinois;
  5. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and
  6. Pfizer Global Research and Development, San Diego, California
  1. Address correspondence and reprint requests to: Samuel Chi-ho Mok, PhD, Laboratory of Gynecologic Oncology, BLI-447, 221 Longwood Avenue, Brigham and Women's Hospital, Boston, MA 02115, USA. Email: scmok{at}


Increased expression of the receptor tyrosine kinase c-Met has been shown to correlate with enhanced cell proliferation, motility, and invasion. The objectives of this study were to characterize total and activated c-Met expression in both normal and malignant human ovarian epithelial cells and to determine the effects of inhibiting the activation of c-Met on ovarian epithelial cell growth, motility, and invasion. Total c-Met was overexpressed in 82 (68%) of 119 ovarian carcinomas, as shown by immunohistochemistry. Quantitative reverse transcription–polymerase chain reaction and Western blot analyses revealed that ovarian carcinoma cell lines had higher levels of c-Met messenger RNA, total protein, and activated protein expression compared to normal ovarian epithelial cell cultures. Using a specific adenosine triphosphate-competitive small-molecule inhibitor, SU11274, activated c-Met was decreased in normal and ovarian carcinoma cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cell growth inhibition directly correlated to the level of activated c-Met detected in each cell line (r=−0.87, P= 0.012). Using modified Boyden chamber assays, ovarian carcinoma cells treated with SU11274 demonstrated significantly decreased cell motility and invasion compared to untreated cells (P= 0.003 and P< 0.001, respectively). These data indicate that c-Met is overexpressed in the majority of malignant ovarian epithelial cells both In vivo and in vitro and that decreasing activated c-Met in vitro can significantly decrease ovarian carcinoma cell growth, motility, and invasion. Developing therapies that specifically inhibit the activation of c-Met may represent a novel therapeutic modality for patients with ovarian carcinomas expressing high levels of c-Met.

  • c-Met
  • gynecological cancers
  • invasion
  • kinase inhibitors
  • metastasis
  • ovarian
  • protein kinase as targets for therapy
  • tumor progression

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