%0 Journal Article
%T Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607
%A Yao Dai
%A Dietmar W Siemann
%J BMC Cancer
%D 2012
%I BioMed Central
%R 10.1186/1471-2407-12-198
%X Cell scattering was tested by monitoring cell morphology after HGF stimulation. Cell migration was examined by both ¡°wound-healing¡± and transwell assasy and invasion was detected by Matrigel-coated transwell assay. Proliferation, survival and anoikis were determined by MTT, colony formation and trypan blue exclusion assay, respectively. Gene and protein expression were assessed by real-time PCR and Western blot, respectively.Although HGF mRNA could be detected in PC-3 cells, the molecular weight of secreted ¡°HGF¡± protein was inconsistent with the functional recombinant HGF. Furthermore, conditioned medium from PC-3 cell cultures was ineffective at triggering either motogenic behavior or c-Met signaling in DU145, another prostate cancer cell line expressing c-Met but lacking basal c-Met activation. PC-3 cells also were not responsive to the anti-HGF neutralizing antibody in experiments assessing proliferation, migration, or c-Met signaling. BMS-777607 treatment with micromolar doses nonetheless led to significant inhibition of multiple PC-3 cell functions including proliferation, clonogenicity, migration and invasion. At the molecular level, BMS-777607 suppressed autophosphorylated c-Met and downstream c-Src and Akt pathways.These results suggest that the constitutive c-Met activation in PC-3 is independent of autocrine stimulation. Because PC-3 cells were responsive to BMS-777607 but not the anti-HGF antibody, the findings also indicate that under circumstances where c-Met is constitutively hyperactive in the absence of functional HGF, targeting the c-Met receptor remains a viable therapeutic option to impede cancer progression.
%K BMS-777607
%K c-Met
%K HGF
%K Neutralizing antibody
%K Prostate cancer
%U http://www.biomedcentral.com/1471-2407/12/198/abstract