TY - JOUR
T1 - Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion
AU - Koon, E. C.
AU - Ma, P. C.
AU - Salgia, R.
AU - Welch, W. R.
AU - Christensen, J. G.
AU - Berkowitz, R. S.
AU - Mok, S. C.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
KW - Gynecological cancers
KW - Invasion
KW - Kinase inhibitors
KW - Metastasis
KW - Ovarian
KW - Protein kinase as targets for therapy
KW - Tumor progression
KW - c-Met
UR - http://www.scopus.com/inward/record.url?scp=51749095291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=51749095291&partnerID=8YFLogxK
U2 - 10.1111/j.1525-1438.2007.01135.x
DO - 10.1111/j.1525-1438.2007.01135.x
M3 - Article
C2 - 18021219
AN - SCOPUS:51749095291
SN - 1048-891X
VL - 18
SP - 976
EP - 984
JO - International Journal of Gynecological Cancer
JF - International Journal of Gynecological Cancer
IS - 5
ER -