Targeting the active β-catenin pathway to treat cancer cells
- 1 November 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 5 (11), 2861-2871
- https://doi.org/10.1158/1535-7163.mct-06-0122
Abstract
The adenomatous polyposis coli or β-catenin genes are frequently mutated in colorectal cancer cells, resulting in oncogenic activation of β-catenin signaling. We tried to establish in vitro and in vivo models for selectively killing human cancer cells with an activated β-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 β-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 β-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 β-catenin. The growth of cells displaying high levels of active β-catenin/Tcf signaling was inhibited after infection with AdTOP-PUMA, whereas that of cells with low levels of β-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]Keywords
This publication has 45 references indexed in Scilit:
- Targeting of autonomous parvoviruses to colon cancer by insertion of Tcf sites in the P4 promoterCancer Gene Therapy, 2005
- Therapeutic Efficacy of PUMA for Malignant Glioma Cells Regardless of p53 StatusHuman Gene Therapy, 2005
- Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatinCancer, 2004
- Optimization of a synthetic β-catenin-dependent promoter for tumor-specific cancer gene therapyMolecular Therapy, 2004
- The suppression of colon cancer cell growth in nude mice by targetingβ-catenin/TCF pathwayOncogene, 2002
- Analysis of the β-Catenin/T Cell Factor Signaling Pathway in 36 Gastrointestinal and Liver Cancer CellsJapanese Journal of Cancer Research, 2002
- A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancerCancer Gene Therapy, 2002
- Protein Kinase G Activates the JNK1 Pathway via Phosphorylation of MEKK1Published by Elsevier BV ,2001
- MECHANISMS OF WNT SIGNALING IN DEVELOPMENTAnnual Review of Cell and Developmental Biology, 1998
- Phase I Study of Direct Administration of a Replication Deficient Adenovirus Vector Containing theE. coliCytosine Deaminase Gene to Metastatic Colon Carcinoma of the Liver in Association with the Oral Administration of the Pro-Drug 5-Fluorocytosine. The New York Hospital-Cornell Medical Center, New York, NYHuman Gene Therapy, 1997