title: Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair.
abstract: Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important. Our recent study demonstrated that Tyr nitration of PP2A stimulates its activity and leads to downregulation of BRCA1 expression. This provides a mechanism for chromosomal instability essential for tumor progression. In the present work, we demonstrated that inhibition of ROS production by generating mitochondrial-electron-transport-deficient cell lines (ρ0cells) or by inhibition of NOX activity with a selective peptide inhibitor significantly reduced PP2A Tyr nitration and its activity in different cancer cell lines. As a result of the decreased PP2A activity, BRCA1 expression was restored along with a significantly enhanced level of DNA HRR. We used TCGA database to analyze the correlation between expressions of the NOX regulatory subunits, NOS isoforms, and BRCA1 in the 3 cancer research studies: breast invasive carcinoma, ovarian cystadenocarcinoma, and lung adenocarcinoma. TCGA database analysis demonstrated that the high expression levels of most of the NOX regulatory subunits responsible for stimulation of NOX1-NOX4 were associated with significant downregulation of BRCA1 expression.
authors: Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, United States.
authors: Aaron
authors: A
authors: Wilson
authors: Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, 401 College Street, Richmond, VA 23298, United States. Electronic address: vasily.yakovlev@vcuhealth.org.
authors: Vasily A
authors: VA
authors: Yakovlev
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043171:Chromosomal Instability; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D030541:Databases, Genetic; D004579:Electron Transport; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D000074624:NADPH Oxidase 1 / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D059767:Recombinational DNA Repair; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D017382:Reactive Oxygen Species; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000074624:NADPH Oxidase 1; C402799:NOX1 protein, human; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D010749:Phosphoprotein Phosphatases
keywords: BRCA1; DNA double-strand break (DSB); Genomic instability; Homologous recombination repair (HRR); NADPH oxidase (NOX); Nitric oxide synthase (NOS); Reactive nitrogen species (RNS); Reactive oxygen species (ROS); Superoxide; TCGA database; ρ(0) cell lines