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Suppression of ß-Catenin Inhibits the Neoplastic Growth of APC-Mutant Colon Cancer Cells¹

Department of Surgery and the A. J. Siteman Cancer Center, The Washington University School of Medicine, St. Louis, Missouri 63110

Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/ß-catenin signaling pathway have been identified in the majorityof colon carcinomas. However, the role of aberrant ß-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate ß-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of ß-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of ß-catenin antisense oligonucleotides down-regulates ß-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of ß-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting ß-catenin may be of use in the therapy of colon cancer.

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