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

in Marine drugs by Karina S Krings, Anastasia Ritchie, Laura Schmitt, Judith Hatzfeld, Gudrun Totzke, Thomas Lenz, María José Mendiburo, Björn Stork, Nicole Teusch, Peter Proksch, Kai Stühler, Lisa Müller, Sebastian Wesselborg

TLDR

  • The study shows that bromoxib, a polybrominated diphenyl ether, exhibits potent anticancer activity by targeting mitochondrial metabolism and the nuclear pore complex.
  • The findings suggest that bromoxib may be a promising agent for treating various types of cancer, as well as HIV-related diseases.

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 spongespecies, 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.

Overview

  • The study focuses on the polybrominated diphenyl ether bromoxib, isolated from marine sponges, and its potential as an anticancer agent.
  • The study used mass spectrometric thermal proteome profiling (TPP) to analyze the effects of bromoxib on cellular proteins and transcription factors.
  • The primary objective is to explore the potential therapeutic applications of bromoxib in treating cancer and its underlying mechanisms.

Comparative Analysis & Findings

  • Bromoxib induces a rapid reduction in the levels of 19 nucleoporins (NUPs) that are part of the nuclear pore complex (NPC).
  • The bromoxib-mediated inhibition of nuclear translocation and gene reporter activity of transcription factors such as NFAT and NF-κB was observed.
  • Bromoxib inhibited the nuclear export of HIV-Tat mRNA and the subsequent import of the HIV-Tat protein into the nucleus, as determined by decreased Tat-dependent gene reporter luciferase activity.

Implications and Future Directions

  • The study highlights the potential of bromoxib as a promising anticancer agent due to its ability to target both mitochondrial metabolism and the NPC.
  • Future studies should focus on exploring the mechanisms of bromoxib's effects on NPC and its potential therapeutic applications in cancer treatment.
  • The study's findings also suggest the possibility of using bromoxib as a treatment for HIV-related diseases and promote further research in this area.
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