Hexachlorophene suppresses beta-catenin expression by up-regulation of Siah-1 in EBV-infected B lymphoma cells.
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.
Min
Hye-Jin
HJ
Department of Nanomedical Engineering, BK21 Nanofusion Technology Team, Pusan National University, Miryang, Gyeongnam, Republic of Korea.
Cho
Il-Rae
IR
Srisuttee
Ratakorn
R
Park
Eun-Hee
EH
Cho
Dae Ho
DH
Ahn
Jin-Hyun
JH
Lee
Im-Soon
IS
Johnston
Randal N
RN
Oh
Sangtaek
S
Chung
Young-Hwa
YH
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
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