Ascorbate Depletion: A Critical Step in Nickel Carcinogenesis? Konstantin Salnikow and Kazimierz S. Kasprzak Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland, USA Abstract Nickel compounds are known to cause respiratory cancer in humans and induce tumors in experimental animals. The underlying molecular mechanisms may involve genotoxic effects ; however, the data from different research groups are not easy to reconcile. Here, we challenge the common premise that direct genotoxic effects are central to nickel carcinogenesis and probably to that of other metals. Instead, we propose that it is formation of metal complexes with proteins and other molecules that changes cellular homeostasis and provides conditions for selection of cells with transformed phenotype. This is concordant with the major requirement for nickel carcinogenicity, which is prolonged action on the target tissue. If DNA is not the main nickel target, is there another unique molecule that can be attacked with carcinogenic consequences? Our recent observations indicate that ascorbate may be such a molecule. Nickel depletes intracellular ascorbate, which leads to the inhibition of cellular hydroxylases, manifested by the loss of hypoxia-inducible factor (HIF) -1 and -2 hydroxylation and hypoxia-like stress. Proline hydroxylation is crucial for collagen and extracellular matrix assembly as well as for assembly of other protein molecules that have collagen-like domains, including surfactants and complement. Thus, the depletion of ascorbate by chronic exposure to nickel could be deleterious for lung cells and may lead to lung cancer. Key words: ascorbate, carcinogenesis, collagens, extracellular matrix, hypoxia-inducible transcription factor, metals, nickel, protein hydroxylation. Environ Health Perspect 113: 577-584 (2005) . doi:10.1289/ehp.7605 available via http://dx.doi.org/ doi:10.1289/ehp.7605 available via http://dx.doi.org/ [Online 10 February 2005] Address correspondence to K. Salnikow, National Cancer Institute at Frederick, Building 538, Room 205 E, Frederick, MD 21702 USA. Telephone: (301) 846-5623. Fax: (301) 846-5946. E-mail: salnikow@ncifcrf.gov The authors declare they have no competing financial interests. Received 24 September ; accepted 9 February 2005. The full version of this article is available for free in HTML or PDF formats. |