title: BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin.
abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) via direct protein-protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.
authors.affiliation: School of Biological Sciences, Plymouth University, Plymouth PL4 8AA, UK.
authors.forename: Deepu
authors.initials: D
authors.lastname: Oommen
authors.affiliation: Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: Yiannakis
authors.affiliation: School of Biological Sciences, Plymouth University, Plymouth PL4 8AA, UK. Electronic address: a.jha@plymouth.ac.uk.
authors.forename: Awadhesh N
authors.initials: AN
authors.lastname: Jha
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001310:Auranofin / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000975:Antioxidants; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D001310:Auranofin; D000111:Acetylcysteine
keywords: Auranofin; BRCA1; DNA damage; Nrf2; Ovarian cancer