Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77

Abstract

Dysregulation of β-catenin turnover due to mutations of its regulatory proteins including APC and p53 is implicated in the pathogenesis of cancer. Thus, intensive effort is being made to search for alternative approaches to reduce abnormally activated β-catenin in cancer cells. Nur77, an orphan member of the nuclear receptor superfamily, plays a role in the growth and apoptosis of cancer cells. Here, we reported that Nur77 could inhibit transcriptional activity of β-catenin by inducing β-catenin degradation via proteasomal degradation pathway that is GSK3β and Siah-1 independent. Nur77 induction of β-catenin degradation required both the N-terminal region of Nur77, which was involved in Nur77 ubiquitination, and the C-terminal region, which was responsible for β-catenin binding. Nur77/ΔDBD, a Nur77 mutant lacking its DNA-binding domain, resided in the cytoplasm, interacted with β-catenin, and induced β-catenin degradation, demonstrating that Nur77-mediated β-catenin degradation was independent of its DNA-binding and transactivation and might occur in the cytoplasm. In addition, we reported our identification of two digitalis-like compounds (DLCs), H-9 and ATE-i2-b4, which potently induced Nur77 expression and β-catenin degradation in SW620 colon cancer cells expressing mutant APC protein in vitro and in animals. DLC-induced Nur77 protein was mainly found in the cytoplasm, and inhibition of Nur77 nuclear export by the CRM1-dependent nuclear export inhibitor leptomycin B or Jun N-terminal kinase inhibitor prevented the effect of DLC on inducing β-catenin degradation. Together, our results demonstrate that β-catenin can be degraded by cytoplasmic Nur77 through their interaction and identify H-9 and ATE-i2-b4 as potent activators of the Nur77-mediated pathway for β-catenin degradation.

Nuclear Import and Export Signals Control the Subcellular Localization of Nurr1 Protein in Response to Oxidative Stress*

“…In connection with the orphan receptors, it has been reported that Nur77, a related member of the orphan receptor family, possesses two NLSs and three NES signals that are implicated in its redistribution from the nucleus to the cytoplasm (44). Of note, it has been reported recently that Nur77 is exported from the nucleus by the exportin CRM1 (36). The presence of several regulatory signals may confer superior versatility to integrate alternative mechanisms of subcellular regulation.…”

Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II–Induced Vascular Remodeling via Downregulation of β-Catenin

“…This result was consistent with the results of previous studies with regard to the interplay between Nur77 and the Wnt/β-catenin signaling pathway in colon cancer cells and in osteoblasts. 20,21,31 This signaling crosstalk may help to identify potential therapeutic targets for vascular remodeling associated with RAS hyperactivation during hypertension, atherosclerosis, vascular injury, restenosis, and aneurysm formation.…”

“…The interplay between Nur77 and the Wnt/β-catenin signaling pathway in cancer cells has been well reported in in vitro and in vivo settings. 20,21 Nur77 significantly suppresses Wnt/β-catenin activity via distinct mechanisms. 20,21 However, no direct information is available about the role of β-catenin in Ang II-induced vascular remodeling, and the mechanism by which β-catenin is regulated.…”

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

“…In colon cancer cell lines, a bile acid carcinogen (deoxycholic acid) has been shown to stimulate b-catenin-dependent increased expression of NR4A1 (10). Conversely, NR4A1 has been shown to promote degradation of cytoplasmic b-catenin in a transcription-independent mechanism, whereas in murine models, NR4A1 has been shown to reduce tumor cell proliferation by transcriptional inhibition of Wnt signaling (11,12).…”