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Research Articles: Therapeutics, Targets, and Development

Targeting the active ß-catenin pathway to treat cancer cells

¹ Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center; ² Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; ³ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Nadir Arber, Director-Integrated Cancer Prevention Center, Tel-Aviv Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel. Phone: 972-3-6974968; Fax: 972-3-6950339. E-mail: narber{at}post.tau.ac.il or nadir{at}tasmc.health.gov.il

Abstract

The adenomatous polyposis coli or ß-catenin genes are frequently mutated in colorectal cancer cells, resulting in oncogenic activation of ß-catenin signaling. We tried to establish in vitro and in vivo models for selectively killing human cancer cells with an activated ß-catenin/T-cell factor (Tcf) pathway. We used a recombinant adenovirus that carries a lethal gene [p53-up-regulated modulator of apoptosis (PUMA)] under the control of a ß-catenin/Tcf–responsive promoter (AdTOP-PUMA) to selectively target human colorectal cancer cells (SW480, HCT116, DLD-1, and LS174T), hepatocellular carcinoma (HepG2), and gastric cancer cells (AGS) in which the ß-catenin/Tcf pathway is activated, and compared its efficiency in killing cancer cells in which this pathway is inactive or only weakly active. AdFOP-PUMA, carrying a mutant Tcf-binding site, was used as control virus. The combined effect of AdTOP-PUMA with several chemotherapeutic agents (5-florouracil, doxorubicin, and paclitaxel) was also evaluated. The effect of AdTOP-PUMA on colorectal cancer cells was also examined in nude mice: SW480 cells were infected with the AdTOP-PUMA and AdFOP-PUMA, and then inoculated s.c. into nude mice. The TOP-PUMA adenovirus inhibited cell growth in a dose-dependent fashion, depending on the signaling activity of ß-catenin. The growth of cells displaying high levels of active ß-catenin/Tcf signaling was inhibited after infection with AdTOP-PUMA, whereas that of cells with low levels of ß-catenin signaling was not. Growth inhibition was associated with induction of apoptosis. Chemotherapy synergistically enhanced the effect of AdTOP-PUMA. A combination of the adenovirus system with standard therapy may improve the efficacy and reduce the toxicity of therapy in humans. [Mol Cancer Ther 2006;5(11):2861–71]

Grant support: Israel Cancer Association (N. Arber), Israel Science Foundation (A. Ben-Ze'ev), and the German-Israel Foundation for Scientific Research and Development (A. Ben-Ze'ev).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: This work was part of the requirements of Hadas Dvory-Sobol for her Ph.D. degree at the Sackler School of Medicine at Tel Aviv University.

Received 3/ 6/06; revised 8/19/06; accepted 9/11/06.

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