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Down‐regulation of MMP‐2 through the p38 MAPK‐NF‐κB‐dependent pathway by aloe‐emodin leads to inhibition of nasopharyngeal carcinoma cell invasion
Author(s) -
Lin MengLiang,
Lu YaoCheng,
Chung JingGung,
Wang ShyangGuang,
Lin HsinTing,
Kang ShangEn,
Tang ChihHsin,
Ko JiunnLiang,
Chen ShihShun
Publication year - 2010
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20652
Subject(s) - biology , p38 mitogen activated protein kinases , pyrrolidine dithiocarbamate , mapk/erk pathway , small interfering rna , cyclin d1 , microbiology and biotechnology , cell growth , cell cycle , ectopic expression , nasopharyngeal carcinoma , kinase , nf κb , cancer research , cell culture , transfection , signal transduction , cell , biochemistry , medicine , genetics , radiation therapy
Abstract Aloe‐emodin (AE), extracted from the rhizome of Rheum palmatum , has an anti‐proliferative effect on different human cancer cell lines. Nonetheless, the underlying mechanism by which AE inhibits nasopharyngeal carcinoma (NPC) cell invasion is still unclear. The results of this study show that treatment of NPC cells with growth suppressive concentrations of AE caused cell cycle arrest at the S‐G 2 /M phase. Coimmunoprecipitation and small interfering RNA (siRNA) studies demonstrated that AE‐induced cell cycle arrest in NPC cells was associated with increasing levels of cyclin B1 bound to cyclin‐dependent kinase 1. The inhibition of NPC cell invasion by AE was evidenced through the suppression of matrix metalloproteinases‐2 (MMP‐2) expression. MMP‐2 promoter activity and cell invasion were inhibited by p38 mitogen‐activated protein kinase (MAPK) siRNA, inhibitor 4‐(4‐Fluorophenyl)‐2‐[4‐(methylsulfinyl)phenyl]‐5‐(4‐pyridyl)‐1H‐imidazole (SB203580), and AE, but not by JNK siRNA and inhibitor 1,9‐pyrazoloanthrone. Treatment with AE, SB203580, NF‐κB inhibitors N‐ p ‐tosyl‐ L ‐phenylalanine chloromethyl ketone (TPCK) and pyrrolidine dithiocarbamate (PDTC) or transfection with p38 MAPK siRNA significantly inhibited NF‐κB transcriptional activity. In addition, TPCK and PDTC treatment inhibited the expression and promoter activity of MMP‐2 and thereby significantly inhibited cell invasion activity. The involvement of p38 MAPK activity in NF‐κB‐mediated MMP‐2 function was further confirmed through the attenuation of p38 MAPK by SB203580 and NF‐κB ectopic expression. Collectively, our results indicate that AE inhibits invasion of NPC cells by suppressing the expression of MMP‐2 via the p38 MAPK‐NF‐κB signaling pathway. © 2010 Wiley‐Liss, Inc.