title: Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death.
abstract: Constitutively active NFκB promotes survival of many cancers, especially T-cell lymphomas and leukemias by upregulating antiapoptotic proteins such as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory proteins (cFLIPs). IAPs and cFLIPs negatively regulate the ripoptosome, which mediates cell death in an apoptotic or necroptotic manner. Here, we demonstrate for the first time, that DMF antagonizes NFκB by suppressing Thioredoxin-1 (Trx1), a major regulator of NFκB transcriptional activity. DMF-mediated inhibition of NFκB causes ripoptosome formation via downregulation of IAPs and cFLIPs. In addition, DMF promotes mitochondrial Smac release and subsequent degradation of IAPs, further enhancing cell death in tumor cells displaying constitutive NFκB activity. Significantly, CTCL patients treated with DMF display substantial ripoptosome formation and caspase-3 cleavage in T-cells. DMF induces cell death predominantly in malignant or activated T-cells. Further, we show that malignant T-cells can die by both apoptosis and necroptosis, in contrast to resting T-cells, which are restricted to apoptosis upon DMF administration. In summary, our data provide new mechanistic insight in the regulation of cell death by targeting NFκB via Trx1 in cancer. Thus, interference with Trx1 activity is a novel approach for treatment of NFκB-dependent tumors.
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Warnken
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Röth
authors.affiliation: Molecular Structure Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karel D
authors.initials: KD
authors.lastname: Klika
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Vobis
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barnert
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Fatmire
authors.initials: F
authors.lastname: Bujupi
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Oberacker
authors.affiliation: Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergy, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Nicolay
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Gülow
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D000069462:Dimethyl Fumarate / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012751:Sezary Syndrome / Q000188:drug therapy; D013879:Thioredoxins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C491203:TXN protein, human; D013879:Thioredoxins; D000069462:Dimethyl Fumarate