Inhibition of c-Met as a therapeutic strategy for esophageal adenocarcinoma.
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-overexpressing EA cell lines (Seg-1, Bic-1, and Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, and 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.
Watson
Gregory A
GA
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Zhang
Xinglu
X
Stang
Michael T
MT
Levy
Ryan M
RM
Queiroz de Oliveira
Pierre E
PE
Gooding
William E
WE
Christensen
James G
JG
Hughes
Steven J
SJ
D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D006801:Humans; D015151:Immunoblotting; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014945:Wound Healing
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met