title: Hexachlorophene suppresses beta-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.
authors.affiliation: Department of Nanomedical Engineering, BK21 Nanofusion Technology Team, Pusan National University, Miryang, Gyeongnam, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Min
authors.forename: Il-Rae
authors.initials: IR
authors.lastname: Cho
authors.forename: Ratakorn
authors.initials: R
authors.lastname: Srisuttee
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Park
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Cho
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Ahn
authors.forename: Im-Soon
authors.initials: IS
authors.lastname: Lee
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D045744:Cell Line, Tumor; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006582:Hexachlorophene / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex; D006582:Hexachlorophene