Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells.
The beta-catenin and APC genes are key components of the Wnt signaling pathway. Mutation of these genes results in increased levels of the beta-catenin protein, which is associated with enhanced cellular proliferation and the development of both colon polyps and colon cancer. Recently, a technique known as RNA interference has been successfully adapted to mammalian cells so that it is now possible to specifically decrease the expression of cellular genes after transfection of annealed small interfering 21-mer RNAs. In the current study, we used small interfering RNA (siRNA) directed against beta-catenin to determine the effects of decreasing the high constitutive levels of this protein in colon cancer cell lines with mutations in either beta-catenin or APC. Our studies demonstrate that siRNA directed against beta-catenin markedly decreased beta-catenin-dependent gene expression and inhibited cellular proliferation as reflected in the reduced growth of these colon cancer cells both in soft agar and in nude mice. These results indicate that siRNA can target specific factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human cancer.
Verma
Udit N
UN
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Surabhi
Rama M
RM
Schmaltieg
Aurelia
A
Becerra
Carlos
C
Gaynor
Richard B
RB
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000628:therapy*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014162:Transfection; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051176:beta Catenin; D012313:RNA; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases