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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Polybrominated diphenyl ethers (PBDEs) are natural products with potent antimicrobial and antineoplastic activity. We have previously shown that the polybrominated diphenyl ether bromoxib (4,5,6-tribromo-2-(2′,4′-dibromophenoxy) phenol), isolated from the marine sponge Dysidea species, exhibits a strong cytotoxic potential in leukemia and lymphoma cells by targeting mitochondrial metabolism. Here, using a mass spectrometric thermal proteome profiling (TPP) approach, we observed that bromoxib induces a rapid reduction in the levels of 19 nucleoporins (NUPs) that are part of the nuclear pore complex (NPC). This apparently affected the functionality of the NPC, as evidenced by the bromoxib-mediated inhibition of the nuclear translocation and subsequent gene reporter activity of transcription factors such as nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF-κB). In addition, bromoxib inhibited the nuclear export of the mRNA of the human immunodeficiency virus transactivator of transcription (HIV-Tat) and the subsequent import of the HIV-Tat protein into the nucleus as determined by the decrease in Tat-dependent gene reporter luciferase activity. Inhibition of nuclear mRNA-export also affected expression of the short-lived anti-apoptotic Bcl-2 protein Mcl-1, which has been shown to induce apoptosis. Thus, its ability to target both mitochondrial metabolism and the NPC renders bromoxib a promising anticancer agent.

Details

Title
The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex
Author
Krings, Karina S 1   VIAFID ORCID Logo  ; Ritchie, Anastasia 2 ; Schmitt, Laura 1 ; Hatzfeld, Judith 1   VIAFID ORCID Logo  ; Totzke, Gudrun 1 ; Lenz, Thomas 3   VIAFID ORCID Logo  ; Mendiburo, María José 1 ; Stork, Björn 1   VIAFID ORCID Logo  ; Teusch, Nicole 4   VIAFID ORCID Logo  ; Proksch, Peter 4 ; Stühler, Kai 3 ; Müller, Lisa 2   VIAFID ORCID Logo  ; Wesselborg, Sebastian 5   VIAFID ORCID Logo 

 Institute for Molecular Medicine I, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany; [email protected] (K.S.K.); [email protected] (L.S.); 
 Institute of Virology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany; [email protected] (A.R.); 
 Molecular Proteomics Laboratory, Biological-Medical-Research Center (BMFZ), Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany 
 Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany; [email protected] (N.T.); 
 Institute for Molecular Medicine I, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany; [email protected] (K.S.K.); [email protected] (L.S.); ; Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), 40225 Duesseldorf, Germany 
First page
108
Publication year
2025
Publication date
2025
Publisher
MDPI AG
e-ISSN
16603397
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3181564210
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.