Hexachlorophene suppresses β-catenin expression by up-regulation of Siah-1 in EBV-infected B lymphoma cells

Abstract

Many studies have shown that the activation of beta-catenin signaling can promote oncogenesis, and it is therefore of interest to find agents that modulate this pathway. Recent work has shown using B lymphoma cells that infection by Epstein-Barr virus (EBV) and expression of its latent membrane protein (LMP)-1, cause increases in the expression of beta-catenin and cellular transformation. Conversely, results from cell-based small molecule screening studies have shown that the antibiotic hexachlorophene can down-regulate beta-catenin in colon cancer cells. Here we report that hexachlorophene also counteracts the elevated beta-catenin levels in EBV-infected B lymphomas. This is associated with restoration in levels of Siah-1 (an E3 ubiquitin ligase that is active in beta-catenin regulation) which had been diminished by LMP-1. Our results suggest that Siah-1 is targeted by both LMP-1 and hexachlorophene with opposite effects. The hexachlorophene modulation of Siah-1 and beta-catenin is independent of p53 and results in reduced expression of cyclin-D1 and c-Myc (target genes of beta-catenin), leading to the growth arrest of B lymphoma cells. From these results we propose that hexachlorophene may provide a novel therapeutic strategy for EBV-infected B lymphoma cells by reducing beta-catenin levels via the restoration of Siah-1.

High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma

“…The Wnt/β-catenin pathway is also significantly involved in the progression of numerous types of carcinomas, including leukemia, myeloma (16)(17)(18)(19) and several subtypes of lymphoma (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). It is known that activation of the Wnt/β-catenin pathway could be important for malignancy of DLBCL.…”

“…The Wnt/β-catenin pathway plays an important role in the progression of leukemia, myeloma (16)(17)(18)(19) and several subtypes of lymphoma, such as Epstein-Barr virus (EBV)-positive Burkitt's lymphoma (BL) (20)(21)(22), mantle cell lymphoma (MCL) (23)(24)(25), cutaneous lymphoma (26), extranodal marginal zone lymphoma (27), ALK-positive anaplastic large cell lymphoma (28), small B-cell lymphoma (29) and DLBCL (9,30). Scientists demonstrated that ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (cic) inhibited the Wnt/β-catenin signaling in OPM-2 myeloma and three lymphoma cell lines (OCI-LY8-LAM-53, SU-DHL-4 and Raji) in vitro, leading to apoptosis and a significant decrease in the viability of lymphoma and its cell lines (30).…”

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders

“…Moreover, a large proportion of B-LPDs show a limited response to chemotherapy. To explore the relevance of PAX5 for drug resistance in B-LPDs, the PAX5-positive IM9 cell line was used as a representative PAX5-positive malignant B-cell line (Brien et al, 2007;Chu et al, 2014;Davis et al, 2010;Min et al, 2009;Shimizu et al, 2006). U266 and RPMI8226 cell lines were employed as PAX5-null multiple myeloma cell lines, and the Daudi cell line was used as a PAX5-positive Burkitt's-lymphomaderived B-lymphoblast representative (Fig.…”

Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the expression of β-catenin, leading to a rapid proliferation of pancreatic cells

“…Next, to address the possibility that the expression levels of β-catenin are directly related to the proliferation of pancreatic cells, hexachlorophene (an inhibitor of β-catenin that was used for our previous study; Min et al, 2009), was used to treat Panc-PAUF and Bx-ConshRNA cells. As seen in Figure 4C, inhibition of β-catenin expression with hexachlorophene suppressed both cell lines despite the presence of PAUF (P ＜ 0.01).…”