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Review
b-Catenin Signaling: Therapeutic Strategies in Oncology
Han Li, Rifat Pamukcu and W. Joseph Thomson
volume 1 | issue 6
november/december 2002Pages: 621-625
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Activated Wnt signaling pathways have been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. As a result, b-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochemical mechanisms yielding inefficient phosphorylation of b-catenin by GSK3b due to APC, b-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/b-catenin/Lef/Tcf signals. Exisulind and analogues are inhibitors of cyclic GMP phosphodiesterases (PDE) that have been shown to activate and induce protein kinase G. The data show PKG regulation of b-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or b-catenin mutations. Exisulind and analogs reduce b-catenin via a novel, GSK3b independent processing mechanism. Activated PKG directly phosphorylate b-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3b, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.