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

Abstract

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.

• Authors: Abner M Mhashilkar, Alexis L Stewart, Kerry Sieger, Heng-Yin Yang, Anis H Khimani, Isao Ito, Yuji Saito, Kelly K Hunt, Elizabeth A Grimm, Jack A Roth, Raymond E Meyn, Rajagopal Ramesh, Sunil Chada
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 8 Issue 2 Pg. 207-19 (Aug 2003) ISSN: 1525-0016 [Print] United States
• PMID: 12907143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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