Suppression of gastric cancer cell growth by targeting the beta-catenin/T-cell factor pathway.
BACKGROUND
Functional activation of beta-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 beta-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 beta-catenin/Tcf signaling.


METHODS
A recombinant adenovirus that carries a lethal gene (p53 up-regulated modulator of apoptosis [PUMA]) under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) was used selectively to target gastric cancer cells (AGS) that posses an active beta-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 beta-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.
Dvory-Sobol
Hadas
H
Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Sagiv
Eyal
E
Liberman
Eliezer
E
Kazanov
Diana
D
Arber
Nadir
N
D000256:Adenoviridae / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051820:TCF Transcription Factors / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D017239:Paclitaxel; D005472:Fluorouracil