Adenomatous polyposis coli (APC)-independent regulation of β-catenin degradation via a retinoid X receptor-mediated pathway

beta-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free beta-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3beta (GSK3beta) or p53-inducible Siah-1. Dysregulation of beta-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of beta-catenin. In this proteasomal pathway, RXR agonists induce degradation of beta-catenin and RXRalpha and repress beta-catenin-mediated transcription. In vivo, beta-catenin interacts with RXRalpha in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3beta inhibitors or deletion of the GSK3beta-targeted sequence from beta-catenin. In APC- and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous beta-catenin via RXRalpha. Interestingly, deletion of the RXRalpha A/B region abolished ligand-induced beta-catenin degradation but not RXRalpha-mediated transactivation. RXRalpha-mediated inactivation of oncogenic beta-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of beta-catenin turnover and related biological events.