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Marine Drugs
Volume 23
Issue 3
10.3390/md23030108
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex

by
Karina S. Krings
1,
Anastasia Ritchie
2,
Laura Schmitt
1,
Judith Hatzfeld
1,
Gudrun Totzke
1,
Thomas Lenz
3,
María José Mendiburo
1,
Björn Stork
1,
Nicole Teusch
4,
Peter Proksch
4,
Kai Stühler
3,
Lisa Müller
2 and
Sebastian Wesselborg
1,5,*
1
Institute for Molecular Medicine I, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany
2
Institute of Virology, Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany
3
Molecular Proteomics Laboratory, Biological-Medical-Research Center (BMFZ), Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany
4
Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Duesseldorf, Universitaetsstraße 1, 40225 Duesseldorf, Germany
5
Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), 40225 Duesseldorf, Germany
*
Author to whom correspondence should be addressed.
Mar. Drugs 2025, 23(3), 108; https://doi.org/10.3390/md23030108 (registering DOI)
Submission received: 3 February 2025 / Revised: 24 February 2025 / Accepted: 27 February 2025 / Published: 28 February 2025
(This article belongs to the Section Marine Pharmacology)
Review Reports Versions Notes

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.
Keywords: marine sponge-derived natural products; polybrominated diphenyl ethers (PBDEs); nucleoporins (NUPs); nuclear pore complex (NPC); nuclear import and export marine sponge-derived natural products; polybrominated diphenyl ethers (PBDEs); nucleoporins (NUPs); nuclear pore complex (NPC); nuclear import and export

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MDPI and ACS Style

Krings, K.S.; Ritchie, A.; Schmitt, L.; Hatzfeld, J.; Totzke, G.; Lenz, T.; Mendiburo, M.J.; Stork, B.; Teusch, N.; Proksch, P.; et al. The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex. Mar. Drugs 2025, 23, 108. https://doi.org/10.3390/md23030108

AMA Style

Krings KS, Ritchie A, Schmitt L, Hatzfeld J, Totzke G, Lenz T, Mendiburo MJ, Stork B, Teusch N, Proksch P, et al. The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex. Marine Drugs. 2025; 23(3):108. https://doi.org/10.3390/md23030108

Chicago/Turabian Style

Krings, Karina S., Anastasia Ritchie, Laura Schmitt, Judith Hatzfeld, Gudrun Totzke, Thomas Lenz, María José Mendiburo, Björn Stork, Nicole Teusch, Peter Proksch, and et al. 2025. "The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex" Marine Drugs 23, no. 3: 108. https://doi.org/10.3390/md23030108

APA Style

Krings, K. S., Ritchie, A., Schmitt, L., Hatzfeld, J., Totzke, G., Lenz, T., Mendiburo, M. J., Stork, B., Teusch, N., Proksch, P., Stühler, K., Müller, L., & Wesselborg, S. (2025). The Polybrominated Diphenyl Ether Bromoxib Disrupts Nuclear Import and Export by Affecting Nucleoporins of the Nuclear Pore Complex. Marine Drugs, 23(3), 108. https://doi.org/10.3390/md23030108

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