Proof-of-principle: oncogenic beta-catenin is a valid molecular target for the development of pharmacological inhibitors.
Activation of beta-catenin is a critical step in the pathogenesis of many common human cancers and is the initiating event in adenocarcinoma of the colon. Because activation of beta-catenin provides a gain-of-function, it is tempting to speculate that specific pharmacological inhibition of activated beta-catenin might reverse the tumorigenic properties of human cancer cells and therefore form the basis of an effective anticancer strategy. In an effort to provide proof-of-principle for such a strategy, we used a novel clonal growth assay based on human somatic cell gene targeting to determine whether activated beta-catenin remains a necessary oncogenic stimulus in advanced human cancer cells. Using this approach, we demonstrate that beta-catenin is a necessary oncogene in human SW48 and DLD1 colon cancer cells but not in HCT116 cells. These data indicate that activated beta-catenin can remain a critical oncogenic stimulus throughout the progression of human colon cancer and suggest that the small molecule inhibitors of activated beta-catenin currently under development will be effective anticancer therapeutics in a subset of malignant colon cancers.
Kim
Jung-Sik
JS
Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20057, USA.
Crooks
Heather
H
Foxworth
Aaron
A
Waldman
Todd
T
D000483:Alleles; D000818:Animals; D002455:Cell Division; D003110:Colonic Neoplasms / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin