title: Thioredoxin stimulates MMP-9 expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 dependent invasion in human MDA-MB-231 breast cancer cells.
abstract: Increased expression of thioredoxin (Trx)-1 and matrix metalloproteinase (MMP)-9 associates with malignant breast cancer progression. Here, we describe a functional relationship between Trx-1 and MMP-9 in promoting MDA-MB-231 breast cancer cell invasive behaviour. Trx-1 overexpression stimulated MMP-9 expression, de-regulated the MMP-9/TIMP-1 equilibrium and augmented MMP-9 involvement in a more invasive phenotype. Trx-1 augmented MMP-9 transcription through NF-κB, AP-1 and SP1 elements; stimulated p50/p65 NF-κB activity and recruitment to the MMP-9 promoter; and facilitated MMP-9 promoter-accessibility to NF-κB by preventing HDAC recruitment and maintaining MMP-9 promoter histone acetylation. Our data provide a functional basis for Trx-1 and MMP-9 association in malignant breast cancer and identify Trx-1 and NF-κB as potentially druggable targets for reducing MMP-9 involvement in malignant behaviour.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: Antonietta R
authors.initials: AR
authors.lastname: Farina
authors.forename: Lucia
authors.initials: L
authors.lastname: Cappabianca
authors.forename: Giuseppina
authors.initials: G
authors.lastname: DeSantis
authors.forename: Natalia
authors.initials: N
authors.lastname: Di Ianni
authors.forename: Pierdomenico
authors.initials: P
authors.lastname: Ruggeri
authors.forename: Marzia
authors.initials: M
authors.lastname: Ragone
authors.forename: Stefania
authors.initials: S
authors.lastname: Merolle
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mackay
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009363:Neoplasm Proteins; C498143:RELA protein, human; C560822:TIMP1 protein, human; C491203:TXN protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D051996:Transcription Factor RelA; D013879:Thioredoxins; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases