17322284

pubmed:Citation

6

Small cell lung cancer (SCLC) is a difficult disease to treat and sometimes has overexpression or mutation of c-Met receptor tyrosine kinase. The effects of c-Met/hepatocyte growth factor (c-Met/HGF, ligand for c-Met) on activation of reactive oxygen species (ROS) was determined. HGF stimulation of c-Met-overexpressing H69 SCLC cells (40 ng/ml, 15 min) resulted in an increase of ROS, measured with fluorescent probe 2'-7'-dichlorofluorescein diacetate (DCFH-DA) or dihydroethidine (DHE) but not in c-Met-null H446 cells. ROS was increased in juxtamembrane (JM)-mutated variants (R988C and T1010I) of c-Met compared with wild-type c-Met-expressing cells. ROS was significantly inhibited by preincubation of SCLC cells with pyrrolidine dithiocarbamate (PDTC, 100 microM) and/or SU11274 (small molecule c-Met tyrosine kinase inhibitor, 2 microM) for 3 h. PDTC and SU11274 also abrogated the HGF proliferative signal and cell motility in a cooperative fashion. H(2)O(2) treatment of SCLC cells (over 15 min) led to phosphorylation of c-Met receptor tyrosine kinase and further upregulated downstream phosphorylation of phospho-AKT, ERK1/2, and paxillin in a dose-dependent manner (125 microM to 500 microM). c-Met is an important target in lung cancer, and the pathways responsible for ROS generation together may provide novel therapeutic intervention.

eng

IM

MEDLINE

1040-0605

Print

NLM

L1488-94

pubmed-meshheading:17322284-Animals, pubmed-meshheading:17322284-Antioxidants, pubmed-meshheading:17322284-Carcinoma, Non-Small-Cell Lung, pubmed-meshheading:17322284-Cell Division, pubmed-meshheading:17322284-Cell Line, Tumor, pubmed-meshheading:17322284-Cell Movement, pubmed-meshheading:17322284-Cell Survival, pubmed-meshheading:17322284-Gene Expression Regulation, Neoplastic, pubmed-meshheading:17322284-Hepatocyte Growth Factor, pubmed-meshheading:17322284-Humans, pubmed-meshheading:17322284-Hydrogen Peroxide, pubmed-meshheading:17322284-Indoles, pubmed-meshheading:17322284-Lung Neoplasms, pubmed-meshheading:17322284-Muridae, pubmed-meshheading:17322284-Phosphorylation, pubmed-meshheading:17322284-Piperazines, pubmed-meshheading:17322284-Proline, pubmed-meshheading:17322284-Proto-Oncogene Proteins c-met, pubmed-meshheading:17322284-Reactive Oxygen Species, pubmed-meshheading:17322284-Signal Transduction, pubmed-meshheading:17322284-Sulfonamides, pubmed-meshheading:17322284-Thiocarbamates, pubmed-meshheading:17322284-Tyrosine

Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural