β-Catenin Signaling: Therapeutic Strategies in Oncology

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Abstract
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, β-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 GSK3β due to APC, β-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/β-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 β-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or β-catenin mutations. Exisulind and analogs reduce β-catenin via a novel, GSK3β independent processing mechanism. Activated PKG directly phosphoryla...

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