Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy.
c-Met is a receptor tyrosine kinase whose activation by hepatocyte growth factor (HGF) can lead to transformation and tumorigenicity in a variety of tumors. We investigated the effects of suppressing c-Met protein expression in human non-small cell lung tumors. Expression plasmids containing either sense or antisense sequences of the human c-met gene were constructed under control of the U6 snRNA promoter. A U6 control plasmid was also constructed that did not contain any c-met sequence. These constructs have been examined both in vitro and in an in vivo tumor xenograft model. The c-Met protein was downregulated by 50-60% in two lung cancer cell lines that were transiently transfected with the c-Met antisense versus U6 control. Tumor cells treated with the c-Met antisense construct also show decreased phosphorylation of c-Met and MAP kinase when exposed to exogenous HGF. Lung cancer cells were grown as xenografts in mice and treated by intratumoral liposome-mediated transfer of the c-Met sense, antisense or U6 control plasmids. The treatment of lung tumors with c-Met antisense versus U6 control plasmid resulted in the downregulation of the c-Met protein expression, a 50% decrease in tumor growth over a 5-week treatment period and an increased rate of apoptosis. These results suggest that targeting the HGF/c-Met pathway may be an effective novel strategy to treat lung cancer patients.
Stabile
L P
LP
Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Lyker
J S
JS
Huang
L
L
Siegfried
J M
JM
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016867:Immunocompromised Host; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D016375:Antisense Elements (Genetics); D012334:RNA, Neoplasm; D019859:Proto-Oncogene Proteins c-met