Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells

Mol Ther. 2004 Apr;9(4):510-8. doi: 10.1016/j.ymthe.2004.01.019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Down-Regulation
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Gelatin / chemistry
  • Gene Transfer Techniques*
  • Genes, Tumor Suppressor
  • Genetic Therapy / methods
  • Humans
  • Immunoblotting
  • Interleukins / biosynthesis*
  • Luciferases / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / prevention & control
  • Neovascularization, Pathologic
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Resting Phase, Cell Cycle
  • Time Factors

Substances

  • Interleukins
  • Proto-Oncogene Proteins
  • interleukin-24
  • Gelatin
  • Luciferases
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9