The Mechanism of Arsenic-Induced Cell Transformation

Arsenic is a naturally existing element which has been recognized as a potent carcinogen. Humans are exposed to it via both environmental contamination and occupational exposure. Epidemiological studies have indicated that people exposed to high levels of arsenic are prone to develop skin, bladder, liver and lung cancers. However, the etiology of arsenic tumorigenesis has not been understood. Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and cellular ability to detoxify the reactive intermediates or repair the resulting damages. In human a major source of reactive oxygen under normal conditions is the leakage of activated oxygen from mitochondria. Advanced studies have established that oxidative stress is involved in arsenic-induced cell damages and cancer. Autophagy is a cell self-defense system functioning in sequestering intracellular dysfunction products, such as long-lived proteins and organelles. Since mitochondrial injury and subsequent ROS elevation have been involved in arsenic cellular toxicity and damaged mitochondria are one of the major targets of autophagy, the interaction of ROS and autophagy may be implicated in arsenic's deleterious effects. Arsenic-induced cell transformation, a process which converts normal cells into a cancer-like state of uncontrolled division, is a critical step in arsenic tumorigenesis. It results from genetic mutations due to genomic damage caused by arsenic exposure. This proposal aims to investigate the mechanism for arsenic-induced cell transformation. It is an innovative study as it is the first investigation of ROS, autophagy and their interaction in arsenic-induced cellular genomic damage. The outcome from this study will provide valuable information for prevention and treatment of cancers caused by arsenic exposure.