Abstract
The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P=0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P=0.0008) and Bcl-XL (P=0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Apoptosis / physiology*
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Carcinoma, Ovarian Epithelial
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Caspases / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cisplatin / administration & dosage
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Cisplatin / pharmacology
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Enzyme Activation / drug effects
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Female
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Hepatocyte Growth Factor / metabolism*
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Humans
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Immunoblotting
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Immunohistochemistry
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Indoles / administration & dosage
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Indoles / pharmacology
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Mice
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Mice, Nude
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Middle Aged
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Neoplasms, Glandular and Epithelial / drug therapy
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Neoplasms, Glandular and Epithelial / metabolism
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Neoplasms, Glandular and Epithelial / pathology
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism*
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RNA Interference
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Sulfones / administration & dosage
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Sulfones / pharmacology
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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Xenograft Model Antitumor Assays
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bcl-X Protein / metabolism
Substances
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5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
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Indoles
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Sulfones
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X-Linked Inhibitor of Apoptosis Protein
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bcl-X Protein
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Proto-Oncogene Proteins c-akt
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Caspases
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Cisplatin