Abstract
Background. c-Met is upregulated in papillary thyroid carcinoma (PTC) and can be an attractive therapeutic target. We tested the effects of the small molecule c-met inhibitor PHA665752 in blocking c-met-dependent phenotypic effects in PTC cell lines. Methods, PTC patient tissues and cell lines were evaluated for c-met expression. The effect of PHA665752 on c-met phosphorylation, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC50 of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.1×, 1×, and 10× IC50 concentrations were obtained. Poly(ADP-ribose) polymerase (PARP) and caspase-9-processing post-PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF-dependent cell invasion and migration in the presence and absence of PHA665752 were done. Results. c-Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c-met phosphorylation, c-met-dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c-met. Conclusions. PHA665752 is an effective and specific inhibi-tor of c-met in PTC cells with high levels of c-met expression.
Original language | English (US) |
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Pages (from-to) | 991-1000 |
Number of pages | 10 |
Journal | Head and Neck |
Volume | 30 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2008 |
Keywords
- C-met
- Cell migration
- PHA665752
- Papillary thyroid carcinoma
- Small molecule inhibitor
ASJC Scopus subject areas
- Otorhinolaryngology
MD Anderson CCSG core facilities
- Flow Cytometry and Cellular Imaging Facility