Targeting Nrf2 in healthy and malignant ovarian epithelial cells: Protection versus promotion

Monique G. P. van der Wijst, Christian Huisman, Archibold Mposhi, Gerard Roelfes, Marianne G. Rots*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
176 Downloads (Pure)

Abstract

Risk factors indicate the importance of oxidative stress during ovarian carcinogenesis. To tolerate oxidative stress, cells activate the transcription factor Nrf2 (Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most cancers, hyperactivity of Nrf2 is observed, and siRNA studies assigned Nrf2 as therapeutic target. However, the cancer-protective role of Nrf2 in healthy cells highlights the requirement for an adequate therapeutic window. We engineered artificial transcription factors to assess the role of Nrf2 in healthy (OSE-C2) and malignant ovarian cells (A2780). Successful NRF2 up- and downregulation correlated with decreased, respectively increased, sensitivity toward oxidative stress. Inhibition of NRF2 reduced the colony forming potential to the same extent in wild-type and BRCA1 knockdown A2780 cells. Only in BRCA1 knockdown A2780 cells, the effect of Nrf2 inhibition could be enhanced when combined with PARP inhibitors. Therefore, we propose that this combination therapy of PARP inhibitors and Nrf2 inhibition can further improve treatment efficacy specifically in BRCA1 mutant cancer cells without acquiring the side-effects associated with previously studied Nrf2 inhibition combinations with either chemotherapy or radiation. Our findings stress the dual role of Nrf2 in carcinogenesis, while offering approaches to exploit Nrf2 as a potent therapeutic target in ovarian cancer. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)1259-1273
Number of pages15
JournalMolecular oncology
Volume9
Issue number7
DOIs
Publication statusPublished - Aug-2015

Keywords

  • Ovarian carcinogenesis
  • Oxidative stress
  • Nrf2 (NFE2L2)
  • BRCA1
  • PARP inhibitor
  • OXIDATIVE DNA-DAMAGE
  • TRANSCRIPTION FACTORS
  • GENE-EXPRESSION
  • PATHWAY ACTIVATION
  • BREAST-CANCER
  • LUNG-CANCER
  • STRESS
  • SURVIVAL
  • COACTIVATOR
  • RESISTANCE

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