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Title: Withaferin A disrupts ubiquitin-based NEMO reorganization induced by canonical NF-κB signaling

The NF-κB family of transcription factors regulates numerous cellular processes, including cell proliferation and survival responses. The constitutive activation of NF-κB has also emerged as an important oncogenic driver in many malignancies, such as activated B-cell like diffuse large B cell lymphoma, among others. In this study, we investigated the impact and mechanisms of action of Withaferin A, a naturally produced steroidal lactone, against both signal-inducible as well as constitutive NF-κB activities. We found that Withaferin A is a robust inhibitor of canonical and constitutive NF-κB activities, leading to apoptosis of certain lymphoma lines. In the canonical pathway induced by TNF, Withaferin A did not disrupt RIP1 polyubiquitination or NEMO–IKKβ interaction and was a poor direct IKKβ inhibitor, but prevented the formation of TNF-induced NEMO foci which colocalized with TNF ligand. While GFP-NEMO efficiently formed TNF-induced foci, a GFP-NEMO{sup Y308S} mutant that is defective in binding to polyubiquitin chains did not form foci. Our study reveals that Withaferin A is a novel type of IKK inhibitor which acts by disrupting NEMO reorganization into ubiquitin-based signaling structures in vivo. - Highlights: • Withaferin A, a NF-κB inhibitor, disrupts signaling induced NEMO localization, a novel point of inhibition. • NEMO can bemore » localized to distinct signaling foci after treatment with TNF. • ABC-type DLCBL cells can be sensitized to apoptosis after treatment with Withaferin A.« less
Authors:
 [1] ;  [2] ;  [2] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [3] ;
  1. McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705 (United States)
  2. (United States)
  3. Department of Medicine, Division of Hematology and Oncology, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 (United States)
Publication Date:
OSTI Identifier:
22462253
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 331; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL PROLIFERATION; IN VIVO; INHIBITION; LIGANDS; LYMPHOMAS; MUTANTS; SIGNALS; TRANSCRIPTION FACTORS