title: Targeting Nrf2 in healthy and malignant ovarian epithelial cells: Protection versus promotion.
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.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1 9713 GZ Groningen, The Netherlands. Electronic address: m.g.p.van.der.wijst@umcg.nl.
authors.forename: Monique G P
authors.initials: MG
authors.lastname: van der Wijst
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1 9713 GZ Groningen, The Netherlands. Electronic address: kriztian.huisman@gmail.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Huisman
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1 9713 GZ Groningen, The Netherlands. Electronic address: a.mposhi@umcg.nl.
authors.forename: Archibold
authors.initials: A
authors.lastname: Mposhi
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. Electronic address: j.g.roelfes@rug.nl.
authors.forename: Gerard
authors.initials: G
authors.lastname: Roelfes
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1 9713 GZ Groningen, The Netherlands. Electronic address: m.g.rots@umcg.nl.
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Rots
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D019398:Genes, BRCA1; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species
keywords: BRCA1; Nrf2 (NFE2L2); Ovarian carcinogenesis; Oxidative stress; PARP inhibitor
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