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Chronic Exposure to Arsenic Causes Increased Cell Survival, DNA Damage, and Increased Expression of Mitochondrial Transcription Factor A (mtTFA) in Human Prostate Epithelial Cells

Arsenic is a known carcinogen, and its exposure is associated with cancers in multiple target organs including the prostate. Whether arsenic causes cancer by increased cell proliferation or cell survival is not clear. Additionally, mitochondria have been shown to play important roles in arsenic-induced DNA damage and carcinogenesis. However, the mechanism of mitochondrial involvement in arsenic-induced cancer is not clear. Therefore, the objectives of this study were to investigate the effect of arsenic on cell proliferation/survival and genotoxicity, and to determine the effect of arsenic on the expression of mitochondrial transcription factor A (mtTFA) in human prostate epithelial cells, RWPE-1. Results of this study revealed that chronic exposure to arsenic causes increased cell survival. Arsenic also induced nuclear DNA damage and mutations in mitochondrial DNA. Expressions of DNA repair genes ERCC6, XPC, OGG1, and reactive oxygen species (ROS) scavenger MnSOD was also altered in arsenic-exposed cells. Arsenic concentration-dependent increased expression of mtTFA and its regulator NRF-1 was observed in arsenic-exposed cells, suggesting that arsenic regulates mitochondrial activity through an NRF-1-dependent pathway. In summary, this study suggests that chronic exposure to arsenic causes DNA damage and increased cell survival that may ultimately result in neoplastic transformation of human prostate epithelial cells. Additionally, this study also provides evidence that arsenic controls mitochondrial function by regulating mtTFA expression.