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Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity

Janakiram R Vangala1, Madison A Ward1, Bader Albalawi1

  • 1Department of Pathology, Virginia Commonwealth University, Richmond, 23298-0662, Virginia.

Molecular Biology of the Cell
|October 22, 2025
PubMed

Insights

Anthracyclines like doxorubicin suppress the Nrf1 transcription factor, which drives resistance to proteasome inhibitors in multiple myeloma. This DNA-damage-independent action may help overcome treatment resistance.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Pharmacology

Background:

  • Proteasome inhibitors are key multiple myeloma treatments, but resistance limits efficacy.
  • The transcription factor Nrf1 (NFE2L1) promotes adaptive resistance by upregulating proteasome and autophagy genes.
  • Understanding resistance mechanisms is crucial for improving cancer therapy.

Purpose of the Study:

  • To identify compounds that suppress Nrf1-mediated adaptive resistance to proteasome inhibitors.
  • To elucidate the mechanism by which anthracyclines inhibit Nrf1 transcriptional activity.
  • To evaluate the therapeutic potential of anthracyclines in overcoming proteasome inhibitor resistance.

Main Methods:

  • Screening for Nrf1 transcriptional suppressors.
  • Assessing Nrf1 binding to antioxidant response elements (AREs).
  • Evaluating Nrf1 processing and nuclear localization.
  • Testing anthracycline effects on proteasome recovery and drug sensitivity in myeloma cells.

Main Results:

  • Anthracyclines, including doxorubicin, were identified as suppressors of Nrf1-driven transcription.
  • Doxorubicin inhibited Nrf1 binding to AREs without affecting Nrf1 processing or localization.
  • Aclarubicin, a non-DNA-damaging anthracycline, also inhibited Nrf1 activity, indicating a DNA-damage-independent mechanism.
  • Doxorubicin cotreatment delayed proteasome recovery and restored sensitivity to carfilzomib in resistant myeloma cells.

Conclusions:

  • Anthracyclines directly inhibit Nrf1-mediated transcriptional induction through a DNA-damage-independent mechanism.
  • Nrf1 plays a significant role in adaptive resistance to proteasome inhibitors.
  • Anthracyclines can serve as chemical tools to probe proteostasis and potentially overcome Nrf1-driven resistance in multiple myeloma.

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