Nrf2, the master redox switch: The Achilles' heel of ovarian cancer?

Monique G. P. van der Wijst, Robert Brown, Marianne G. Rots*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

41 Citations (Scopus)

Abstract

Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2I2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1-CUL3-RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies. (C) 2014 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)494-509
Number of pages16
JournalBiochimica et biophysica acta-Reviews on cancer
Volume1846
Issue number2
DOIs
Publication statusPublished - Dec-2014

Keywords

  • Reactive oxygen species
  • Oxidative stress
  • Nrf2
  • Ovarian cancer
  • Cancer therapy
  • Mutations
  • ANTIOXIDANT RESPONSE ELEMENT
  • SQUAMOUS-CELL CARCINOMAS
  • GRADE SEROUS CARCINOMA
  • NF-KAPPA-B
  • OXIDATIVE STRESS
  • GENE-EXPRESSION
  • BREAST-CANCER
  • ESTROGEN-RECEPTOR
  • DNA DEMETHYLATION
  • IN-VIVO

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