The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis

• Published in: Oncogene Vol. 27; no. 31; pp. 4353 - 4362
• Main Authors: Frohlich, D A, McCabe, M T, Arnold, R S, Day, M L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-07-2008; Nature Publishing; Nature Publishing Group
• Subjects: Animal models; Animals; Antioxidants; Apoptosis; Biological and medical sciences; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Deoxyribonucleic acid; Detoxification; DNA; DNA binding proteins; DNA Damage; DNA microarrays; Enzymes; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transformation; Genetics; Glutathione; Glutathione transferase; Glutathione Transferase - metabolism; Gynecology. Andrology. Obstetrics; Health aspects; Human Genetics; Humans; Internal Medicine; Leucine zipper proteins; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Molecular and cellular biology; Nephrology. Urinary tract diseases; NF-E2-Related Factor 2 - metabolism; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Oxidation; Oxidative stress; Physiological aspects; Prostate cancer; Prostatic Neoplasms - diagnosis; Prostatic Neoplasms - pathology; Reactive Oxygen Species; Retinoblastoma Protein - metabolism; Risk factors; Tumorigenesis; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United States; prostate cancer; tumorigenesis; Nrf2; DNA damage; oxidative stress; Oxidative stress; Urinary system disease; Prostate disease; Malignant tumor; Carcinogenesis; Free radical; DNA; Lesion; Transcription factor; Urogenital system; Male genital diseases; Prostate cancer; Prostate; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.79

The impact of oxidative stress in human cancer has been extensively studied. It is accepted that elevated reactive oxygen species (ROS) promote mutagenic DNA damage. Even with an extensive armament of cellular antioxidants and detoxification enzymes, alterations to DNA occur that initiate cellular transformation. Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). By analysing 10 human prostate cancer microarray data sets, we have determined that Nrf2 and members of the glutathione-
S
-transferase (GST) mu family are extensively decreased in human prostate cancer. Using the TRAMP transgene and Rb and Nrf2 knockout murine models, we demonstrated that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumorigenesis. Based on overwhelming data from clinical samples and the current functional analysis, we propose that the disruption of the Nrf2-antioxidant axis leads to increased oxidative stress and DNA damage in the initiation of cellular transformation in the prostate gland.