Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells.
We have previously observed the suppression of lung tumor growth in response to overexpression of melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24; approved gene symbol IL24) in vitro and in vivo. MDA-7/IL-24 exerts its tumor-suppressive effects by multiple mechanisms, including the activation of the caspase cascade and the inhibition of angiogenesis. In this study, we used an adenoviral vector (Ad-mda7) to examine the effect of the ectopic production of MDA-7/IL-24 on cell migration and invasion by human non-small-cell lung carcinoma cells. Lung tumor cells (H1299 and A549) treated in vitro with Ad-mda7 migrated and invaded less than cells treated with phosphate-buffered saline (PBS) or Ad-Luc (vector control). MDA-7/IL-24 inhibited migration and invasion by down-regulating the production of phosphatidylinositol 3-kinase/protein kinase B, focal adhesion kinase, and matrix metalloproteinase-2 and -9 relative to PBS and Ad-Luc. Furthermore, tumor cells treated with Ad-mda7 ex vivo or with DOTAP:Chol-mda7 complex in vivo formed significantly fewer tumors in an experimental lung metastasis model. These results show that MDA-7/IL-24 inhibits invasion and migration by lung cancer cells by down-regulating proteins associated with these processes, resulting in reduced metastasis. Thus, Ad-mda7 should be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis.
Ramesh
Rajagopal
R
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. rramesh@mdanderson.org
Ito
Isao
I
Gopalan
Began
B
Saito
Yuji
Y
Mhashilkar
Abner M
AM
Chada
Sunil
S
D000256:Adenoviridae / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005780:Gelatin / Q000737:chemistry; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D007378:Interleukins / Q000096:biosynthesis*; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016192:Resting Phase, Cell Cycle; D013997:Time Factors; D000099180:Interleukin-24
D020169:Caspases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005780:Gelatin; D007378:Interleukins; D008156:Luciferases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099180:Interleukin-24; C496050:PTK2 protein, human