MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells

Mol Ther. 2003 Aug;8(2):207-19. doi: 10.1016/s1525-0016(03)00170-9.


mda-7 is a novel tumor suppressor with cytokine properties. Adenoviral mda-7 (Ad-mda7) induces apoptosis and cell death selectively in tumor cells. The molecular mechanisms underlying the anti-tumor activity of Ad-mda7 in breast and lung cancer lines were investigated. Microarray analyses implicated both the beta-catenin and the PI3K signaling pathways. Ad-mda7 treatment increased protein expression from tumor suppressor genes, including E-cadherin, APC, GSK-3beta, and PTEN, and decreased expression of proto-oncogenes involved in beta-catenin and PI3K signaling. Ad-mda7 caused a redistribution of cellular beta-catenin from the nucleus to the plasma membrane, resulting in reduced TCF/LEF transcriptional activity, and upregulated the E-cadherin-beta-catenin adhesion complex in a tumor cell-specific manner. Expression of the PI3K pathway members (p85 PI3K, FAK, ILK-1, Akt, and PLC-gamma) was downregulated and expression of the PI3K antagonist PTEN was increased. Consistent with this result, pharmacological inhibition of PI3K by wortmannin did not abrogate killing by Ad-mda7. Killing of breast cancer cells by Ad-mda7 required both MAPK and MEK1/2 signaling pathways, whereas these pathways were not essential for MDA-7-mediated killing in lung cancer cells. Thus, in breast and lung tumor cells MDA-7 protein expression modulates cell-cell adhesion and intracellular signaling via coordinate regulation of the beta-catenin and PI3K pathways.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Death
  • Cell Line, Tumor
  • Cell Movement
  • Cytoskeletal Proteins / antagonists & inhibitors
  • Cytoskeletal Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding
  • Proto-Oncogenes / genetics
  • Signal Transduction*
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism*
  • beta Catenin


  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Interleukins
  • Phosphoinositide-3 Kinase Inhibitors
  • Trans-Activators
  • beta Catenin
  • interleukin-24