MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells.
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.
Mhashilkar
Abner M
AM
Introgen Therapeutics, Inc., Houston, Texas, 77030, USA.
Stewart
Alexis L
AL
Sieger
Kerry
K
Yang
Heng-Yin
HY
Khimani
Anis H
AH
Ito
Isao
I
Saito
Yuji
Y
Hunt
Kelly K
KK
Grimm
Elizabeth A
EA
Roth
Jack A
JA
Meyn
Raymond E
RE
Ramesh
Rajagopal
R
Chada
Sunil
S
D000256:Adenoviridae / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D016923:Cell Death; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011519:Proto-Oncogenes / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin; D000099180:Interleukin-24
D015820:Cadherins; D003598:Cytoskeletal Proteins; D007378:Interleukins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015534:Trans-Activators; D051176:beta Catenin; D000099180:Interleukin-24; C495270:CTNNB1 protein, human