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Suppression of gastric cancer cell growth by targeting the β‐catenin/T‐cell factor pathway
Author(s) -
DvorySobol Hadas,
Sagiv Eyal,
Liberman Eliezer,
Kazanov Diana,
Arber Nadir
Publication year - 2007
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.22416
Subject(s) - puma , cancer , cancer research , cancer cell , apoptosis , cell growth , carcinogenesis , cell cycle , medicine , adenomatous polyposis coli , biology , colorectal cancer , genetics
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. Cancer 2007. © 2006 American Cancer Society.