Molecular Mechanisms of Nickel Carcinogenesis

Abstract

Carcinogenic, water-insoluble Ni compounds are phagocytized by cells; and the particles undergo dissolution inside the cell, releasing Ni ions that interact with chromatin. Ni produces highly selective damage to heterochromatin. The longest contiguous region of heterochromatin in the Chinese hamster genome is found on the q arm of the X chromosome, and this region is selectively damaged by Ni. More than half of the male mice in which there were Ni-induced transformations of Chinese hamster cells exhibited complete deletion of the long arm of the X chromosome. The introduction of a normal X chromosome into these cells resulted in cellular senescence, suggesting that the Ni interacted with Chinese hamster genome to inactivate a senescence gene. Investigations were conducted into the mechanisms by which Ni produced damage to chromatin. Ni ions have a much higher affinity for proteins and amino acids than for DNA (by five to seven orders of magnitude). Therefore, Ni interacted with chromatin because of the protein present, not because of its reactivity for DNA. Studies have shown that Ni produced an increase in oxidative products in cells as indicated by oxidation of the fluorescent dye dichlorofluorescein; Ni has also been shown to produce oxidation of proteins in cells, as measured by carbonyl formation. Ni cross-linked certain amino acids and proteins to DNA. These covalent cross-links were not dissociated by EDTA and are inconsistent with direct Ni involvement, but they are consistent with Ni acting catalytically. Using subtractive hybridization, we have isolated a number of clones that are expressed in normal but not in Ni-transformed cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Downregulation of Cap43 gene by von Hippel‐Lindau tumor suppressor protein in human renal cancer cells

“…Numerous studies have confirmed that nickel compounds induce cell transformation and tumor formation in experimental animals, indicating the carcinogenic potency of nickel compounds [31][32][33][34] However, the molecular mechanisms by which nickel causes cancers are not well understood. Nickel compounds might increase free intracellular calcium 35 and reactive oxygen species.…”

Toxicological interactions between nickel and radiation on chromosome damage and repair.

“…The properties of some of these compounds have been studied extensively and these findings have been summarized in several recent reviews (13)(14)(15). Among the different kinds of nickel compounds, insoluble compounds are usually more carcinogenic than the soluble ones.…”

Molecular mechanisms in nickel carcinogenesis: modeling Ni(II) binding site in histone H4.

“…Numerous studies point to the cell nucleus as the site of nickel attack (12)(13)(14), thus, the identification of cellular-nuclear binding sites for nickel and the basic chemical activities resulting from the binding modes are objectives essential to understanding the mechanisms involved.…”

“…Eventually the cells undergo neoplastic transformation, and cancer develops in a process that may take many years. The carcinogenic potency of nickel compounds is consistently related to the ability of Ni(II) to access chromatin and cause multiple types of cellularnuclear damage via direct or indirect mechanisms, including a) promutagenic DNA damage, that is, oxidative damage to nucleobases as well as DNA strand breaks (8,9); b) impairment of DNA repair mechanisms by nickel (10,11); and c) epigenetic effects in chromatin, such as chromatin condensation and inhibition of histone H4 acetylation (12)(13)(14)(15).…”