Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma
| Autor: | Gregory A. Watson, Xinglu Zhang, Michael T. Stang, Ryan M. Levy, Pierre E. Queiroz de Oliveira, William E. Gooding, James G. Christensen, Steven J. Hughes |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: | |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 8, Iss 11, Pp 949-955 (2006) |
| Druh dokumentu: | article |
| ISSN: | 1476-5586 1522-8002 |
| DOI: | 10.1593/neo.06499 |
| Popis: | The hepatocyte growth factor (HGF) receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA), yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K)/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition. |
| Databáze: | Directory of Open Access Journals |
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