beta-Catenin signaling: therapeutic strategies in oncology.
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.
Li
Han
H
Cell Pathways, Inc., Horsham, Pennsylvania, USA. HLi@cellpathways.com
Pamukcu
Rifat
R
Thompson
W Joseph
WJ
D011125:Adenomatous Polyposis Coli / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060466:Axin Protein; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D008495:Medical Oncology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D013467:Sulindac / Q000031:analogs & derivatives / Q000627:therapeutic use; D015534:Trans-Activators / Q000502:physiology*; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; D013467:Sulindac; C025463:sulindac sulfone