Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion.

摘要: The c-MET receptor can be overexpressed, amplified, or mutated in solid tumours including small cell lung cancer (SCLC). In c-MET-overexpressing SCLC line NCI-H69, hepatocyte growth factor (HGF) dramatically induced phosphorylation at phosphoepitopes pY1230/1234/1235 (catalytic tyrosine kinase), pY1003 (juxtamembrane), and also of paxillin pY31 (CRKL-binding site). We utilised a global proteomics phosphoantibody array approach to identify further c-MET/HGF signal transduction intermediates SCLC. Strong HGF induction specific sites phosphoproteins involved was detected, namely adducin-α [S724], adducin-γ [S662], CREB [S133], ERK1 [T185/Y187], ERK1/2 [T202/Y204], ERK2 MAPKK (MEK) 1/2 [S221/S225], 3/6 [S189/S207], RB [S612], RB1 [S780], JNK [T183/Y185], STAT3 [S727], focal adhesion kinase (FAK) [Y576/S722/S910], p38α-MAPK [T180/Y182], AKT1[S473] [T308]. Conversely, inhibition by protein C (PKC), R (PKR), CDK1 identified. Phosphoantibody-based immunohistochemical analysis tumour tissue microarray established the role biology. This supports activation invasive front progression invasion involving FAK AKT downstream. serves as an attractive therapeutic target SCLC, shown through interfering RNA (siRNA) selective prototype inhibitor SU11274, inhibiting itself its downstream molecules such AKT, S6 kinase, ERK1/2. Investigation mechanisms and, ultimately, metastasis would very useful with these molecules.