Mechanism of Arsenic Induced Preservation of Keratinocyte Proliferative Potential
University of California, Davis, 2006 - 240 pages
Arsenic contaminates the drinking water of millions of individuals with chronic exposure commonly resulting in skin cancer. Inorganic arsenic, which exists in two oxidation states and is further metabolized in vivo, is the primary form of arsenic ingested with drinking water. We demonstrate that arsenite, the trivalent species, is most likely responsible for the effects observed in keratinocytes. An animal model where arsenic treatment alone results in skin cancer has been elusive, giving rise to the hypothesis other factors are necessary for carcinogenesis to occur. We demonstrated that low micromolar concentrations of sodium arsenite preserved the colony forming efficiency (CFE) of cultured keratinocytes. Further, rapidly adhering colony-forming cells (RACs), representative of keratinocytes with the highest proliferative potential, or the putative stem cell population, was also elevated with arsenite treatment. Using CFE and RACs as an endpoint, we investigated signaling pathways responsible for the observed effects. Experimental evidence indicated arsenite opposes the negative action of insulin, which promotes exit from the germinative pool into terminal differentiation. The EGFR is central to this response, as inhibiting EGFR activity reversed the effect of arsenite or insulin removal on proliferative potential. Arsenite activation of the EGFR also led to the stabilization, nuclear accumulation, and elevated activity of beta-catenin. Stabilization of beta-catenin is ultimately responsible for arsenite preservation of the RAC population. Addition of EGF or the PI 3-kinase inhibitor LY294002 to arsenite treated cultures resulted in a greater effect on beta-catenin and CFE. Antimony, a metalloid with similar toxicological properties as arsenite, yielded results similar to that of arsenite providing additional insight into the mechanism of arsenic action. Preservation of proliferative potential is a direct answer to how arsenite may be acting as a co-carcinogen and elucidating the biochemical processes underlying this response may stimulate solutions to arsenic induced carcinogenesis.
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