title: Ascorbate depletion: a critical step in nickel carcinogenesis?
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)-1alpha and -2alpha 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.
authors.affiliation: Laboratory of Comparative Carcinogenesis, Building 538, Room 205 E., National Cancer Institute at Frederick/NIH, Frederick, MD 21702, USA. salnikow@ncifcrf.gov
authors.forename: Konstantin
authors.initials: K
authors.lastname: Salnikow
authors.forename: Kazimierz S
authors.initials: KS
authors.lastname: Kasprzak
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D006706:Homeostasis; D006801:Humans; D006900:Hydroxylation; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D009532:Nickel / Q000378:metabolism / Q000633:toxicity*; D011392:Proline / Q000378:metabolism; D011485:Protein Binding; D051381:Rats
chemical_list: D000975:Antioxidants; D009532:Nickel; D011392:Proline; D001205:Ascorbic Acid