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beta-Catenin signaling: therapeutic strategies in oncology
Han Li1, Rifat Pamukcu, W Joseph Thompson
1Cell Pathways, Inc., Horsham, Pennsylvania, USA. HLi@cellpathways.com
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, beta-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochemical mechanisms yielding inefficient phosphorylation of beta-catenin by GSK3beta due to APC, beta-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/beta-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 beta-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or beta-catenin mutations. Exisulind and analogs reduce beta-catenin via a novel, GSK3beta independent processing mechanism. Activated PKG directly phosphorylate beta-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3beta, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects.
Insights
Exisulind and analogs target Wnt signaling in cancer by activating protein kinase G (PKG). This novel approach induces cancer cell apoptosis through a GSK3beta-independent mechanism, degrading beta-catenin.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant Wnt signaling, characterized by beta-catenin accumulation, drives proliferation in multiple cancers (colon, liver, endometrium, ovary, prostate, stomach).
- Mutations in APC, beta-catenin, or axin disrupt beta-catenin phosphorylation by GSK3beta, leading to oncogenic pathway activation.
- Targeting the oncogenic APC/beta-catenin/Lef/Tcf axis presents a therapeutic opportunity for Wnt-driven cancers.
Purpose of the Study:
- To investigate the mechanism of exisulind and its analogues in modulating Wnt signaling and inducing apoptosis in cancer cells.
- To determine if exisulind's effects are mediated by protein kinase G (PKG) and if this pathway is independent of GSK3beta and APC mutations.
- To establish exisulind and analogues as a superior therapeutic strategy for cancers with Wnt pathway defects.
Main Methods:
- Treatment of colon cancer cells with exisulind and analogues.
- Analysis of beta-catenin levels and phosphorylation.
- Assessment of protein kinase G (PKG) activation and its role in beta-catenin degradation.
- Investigation of the involvement of GSK3beta and APC in the exisulind-mediated pathway.
Main Results:
- Exisulind and analogues activate protein kinase G (PKG).
- Activated PKG directly phosphorylates beta-catenin, leading to its proteasome-dependent degradation.
- This degradation mechanism is independent of GSK3beta and APC, circumventing common Wnt pathway mutations.
- Exisulind treatment induced apoptosis in colon cancer cells with APC or beta-catenin mutations.
Conclusions:
- Exisulind and analogues offer a novel therapeutic strategy by targeting Wnt signaling through a GSK3beta-independent mechanism involving PKG activation.
- The ability to reduce beta-catenin via PKG-mediated degradation provides a superior approach to overcome molecular defects in Wnt signaling pathways.
- These findings support the development of exisulind and analogues for treating various cancers driven by aberrant Wnt signaling.