1. ¹Introgen Therapeutics, Inc., Houston, Texas 77030, USA
2. ²Perkin–Elmer NEN Life Sciences, Inc., Boston, Massachusetts 01720, USA
3. ³Section of Thoracic Molecular Oncology and Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
4. ⁴Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
5. ⁵Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
6. ⁶Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence: Sunil Chada, Introgen Therapeutics, 2250 Holcombe Boulevard, Houston, TX 77030, USA. Fax: (713) 797-1349. E-mail: s.chada@introgen.com

^*Present address: Molecular Discovery Systems, Ventana Medical Systems, Inc., Tucson, AZ 85737.

Received 6 February 2003; Accepted 2 May 2003.

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 -catenin and the PI3K signaling pathways. Ad-mda7 treatment increased protein expression from tumor suppressor genes, including E-cadherin, APC, GSK-3, and PTEN, and decreased expression of proto-oncogenes involved in -catenin and PI3K signaling. Ad-mda7 caused a redistribution of cellular -catenin from the nucleus to the plasma membrane, resulting in reduced TCF/LEF transcriptional activity, and upregulated the E-cadherin–-catenin adhesion complex in a tumor cell-specific manner. Expression of the PI3K pathway members (p85 PI3K, FAK, ILK-1, Akt, and PLC-) 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 -catenin and PI3K pathways.