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Constitutive activation of met kinase in non‐small‐cell lung carcinomas correlates with anchorage‐independent cell survival
Author(s) -
Qiao Hui,
Hung Wesley,
Tremblay Eric,
Wojcik Joanna,
Gui Jin,
Ho Janet,
Klassen Jennifer,
Campling Barbara,
Elliott Bruce
Publication year - 2002
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10239
Subject(s) - cancer research , hepatocyte growth factor , paracrine signalling , cell culture , tyrosine kinase , biology , receptor tyrosine kinase , cell , lung cancer , kinase , medicine , signal transduction , receptor , microbiology and biotechnology , genetics
Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over‐expressed in non‐small‐cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine‐phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage‐independent conditions, and correlated with phosphatidyl inositol 3‐kinase‐dependent cell survival. Immunoreactive HGF‐like protein was secreted by two Met‐positive and two Met‐negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine‐phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met‐negative NSCLC cell line: none of the conditioned media from Met‐expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF‐independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met‐positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC. J. Cell. Biochem. 86: 665–677, 2002. © 2002 Wiley‐Liss, Inc.