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 β-catenin and the PI3K signaling pathways. Ad-mda7 treatment increased protein expression from tumor suppressor genes, including E-cadherin, APC, GSK-3β, and PTEN, and decreased expression of proto-oncogenes involved in β-catenin and PI3K signaling. Ad-mda7 caused a redistribution of cellular β-catenin from the nucleus to the plasma membrane, resulting in reduced TCF/LEF transcriptional activity, and upregulated the E-cadherin-β-catenin adhesion complex in a tumor cell-specific manner. Expression of the PI3K pathway members (p85 PI3K, FAK, ILK-1, Akt, and PLC-γ) 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 β-catenin and PI3K pathways.
Original language | English (US) |
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Pages (from-to) | 207-219 |
Number of pages | 13 |
Journal | Molecular Therapy |
Volume | 8 |
Issue number | 2 |
DOIs | |
State | Published - Aug 1 2003 |
Keywords
- Adenovirus
- Adhesion
- Apoptosis
- Cancer gene therapy
- IL-24
- Kinases
- PI3K
- Signaling
- mda-7
- β-catenin
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery