Supression of gastric cancer cell growth by targeting the β-catenin/T-cell factor pathway

Hadas Dvory-Sobol, Eyal Sagiv, Eliezer Liberman, Diana Kazanov, Nadir Arber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

BACKGROUND. Functional activation of β-catenin/T-cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. Recently, it was demonstrated that adenomatous polyposis coli or β-catenin genes are mutated frequently in gastric cancer cells. The objective of the current study was to use a gene-targeting approach to kill human gastric cancer cells selectively with activated β-catenin/Tcf signaling. METHODS. 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) was used selectively to target gastric cancer cells (AGS) that posses an active β-catenin/Tcf pathway. The combined effect of AdTOP-PUMA and several chemotherapeutic agents (5-florouracil, doxorubicin, paclitaxel) also was evaluated. Cell viability was measured by methylene blue assay, protein expression was measured by Western blot analysis, and cell cycle and apoptosis were evaluated by fluorescent-activated cell sorter analysis. RESULTS. The TOP-PUMA adenovirus inhibited AGS cell growth in a dose- and time-dependent fashion. Growth inhibition was associated with the up-regulation of PUMA expression and the induction of apoptosis. Chemotherapy synergistically enhanced the killing effect of AdTOP-PUMA. CONCLUSIONS. Selective targeting of gastric cancer cells with the activated β-catenin pathway may be a novel and effective therapy in gastric cancer. Combination of this gene-therapy approach with standard therapy may improve efficacy and reduce toxicity.

Original languageEnglish
Pages (from-to)188-197
Number of pages10
JournalCancer
Volume109
Issue number2
DOIs
StatePublished - 15 Jan 2007

Keywords

  • Adenovirus
  • Gastric cancer
  • Gene therapy
  • T-cell factor
  • β-catenin

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