Certain transition metals, including nickel, chromium, cadmium, and copper, are carcinogenic to humans and/or animals. Their effects include cancer in the progeny of fathers exposed to welding fumes and other metal dusts. However, mechanisms of the carcinogenic activity of these metals remain obscure. In recent years, we have been testing a hypothesis that one such mechanism would involve metal-mediated oxidative damage to DNA and nuclear proteins. In 1998/99 we continued mechanistic studies of that hypothesis. Our investigations on transition metals interactions with protamine HP2 were directed towards binding of Zn(II) and Ni(II) to its model peptides HP2 1-15, HP2 1-25, HP2 26-40, HP2 37-47, HP2 43-57, and the effects of this binding on association of the peptides with a 20-mer double stranded oligonucleotide. Zn(II) was found to bind to all these peptides and increase their association with the oligonucleotide, although with different strength. Zn(II) binding sites differed from those for Ni(II).Using synthetic model peptides, we continued to investigate Ni(II) interactions with the core histones. The formation of a strong complex at pH 7 and above with the TESHHK motif in the C-terminal ?tail? of histone H2A and hydrolysis of this motif by Ni(II) were confirmed in longer peptides, acetyl-TESHHKAKGK, and a 34-mer peptide (H2A 1-34) modeling the entire ?tail?. The primary complexes lack significant oxidation-mediating activity towards DNA. However, a secondary complex formed between Ni(II) and the SHHKAKGK product of hydrolysis of the primary complexes is redox-active and is capable of enhancing oxidative damage by hydrogen peroxide to plasmid DNA (single strand breaks and base oxidation). Also, this complex is degraded by hydrogen peroxide, especially at its histidine and serine residues. Since the physiological roles of the histone ?tail? include locking interactions with other histones and DNA, the observed truncation of this ?tail? by Ni(II) may affect gene expression. The redox activity of the cut-off product may enhance promutagenic damage to DNA.Another investigation focused on 8-oxo-dGTPases, a class of enzymes preventing incorporation of promutagenic 8-oxo-dGTP into DNA. Our former experiments revealed strong inhibition by Cd(II) and weak inhibition by Ni(II) of the isolated mammalian enzyme. Using our newly developed in vivo assay for 8-oxo-dGTPase we confirmed the inhibition of its activity by Cd(II) in the testes of rats exposed to Cd(II), but not Ni(II). The inhibition was accompanied by a significant increase of the promutagenic 8-oxo-dG lesion in testicular DNA. The epigenetic toxicity of Ni(II) was studied in cultured CHO cells. Ni(II) caused cell cycle arrest at G2/M phase and apoptosis. It did not, however, affect the expression of p53 protein. Using the differential display technique, we found that the exposure of cells to Ni(II) resulted in up-regulation of the H ferritin and hSNF2H genes, and down-regulation of the vimentin gene. All the results indicate that Ni(II) and, perhaps, other carcinogenic metals can act through both genetic and epigenetic mechanisms involving oxidative damage and other chemical mechanisms. In addition, our research provides an experimental basis for collaborative studies on oxidative damage by other carcinogenic insults (see projects ZO1 BC 05301 and ZO1 BC 05302). - 8-oxo-dG, Chemical carcinogenesis, dGTPase, DNA damage, DNA repair, Histones, Metal carcinogenesis, Nickel, Nuclear proteins, Protamines,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC004582-24
Application #
6289067
Study Section
Special Emphasis Panel (LCC)
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kaczmarek, Monika; Timofeeva, Olga A; Karaczyn, Aldona et al. (2007) The role of ascorbate in the modulation of HIF-1alpha protein and HIF-dependent transcription by chromium(VI) and nickel(II). Free Radic Biol Med 42:1246-57
Romanowska, Malgorzata; Kikawa, Keith D; Fields, Janet R et al. (2007) Effects of selenium supplementation on expression of glutathione peroxidase isoforms in cultured human lung adenocarcinoma cell lines. Lung Cancer 55:35-42
Romanowska, Malgorzata; Maciag, Anna; Smith, Andrew L et al. (2007) DNA damage, superoxide, and mutant K-ras in human lung adenocarcinoma cells. Free Radic Biol Med 43:1145-55
Topol, Igor A; Nemukhin, Alexander V; Salnikow, Konstantin et al. (2006) Quantum chemical modeling of reaction mechanism for 2-oxoglutarate dependent enzymes: effect of substitution of iron by nickel and cobalt. J Phys Chem A 110:4223-8
Waalkes, Michael P; Liu, Jie; Kasprzak, Kazimierz S et al. (2006) Hypersusceptibility to cisplatin carcinogenicity in metallothionein-I/II double knockout mice: production of hepatocellular carcinoma at clinically relevant doses. Int J Cancer 119:28-32
Karaczyn, Aldona; Ivanov, Sergey; Reynolds, Mindy et al. (2006) Ascorbate depletion mediates up-regulation of hypoxia-associated proteins by cell density and nickel. J Cell Biochem 97:1025-35
Pi, Jingbo; He, Yuying; Bortner, Carl et al. (2005) Low level, long-term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: potential role in skin co-carcinogenesis. Int J Cancer 116:20-6
Waalkes, Michael P; Liu, Jie; Kasprzak, Kazimierz S et al. (2005) Metallothionein-I/II double knockout mice are no more sensitive to the carcinogenic effects of nickel subsulfide than wild-type mice. Int J Toxicol 24:215-20
Kaczmarek, Piotr; Jezowska-Bojczuk, Malgorzata; Bal, Wojciech et al. (2005) Determination of the stability constants and oxidation susceptibility of nickel(II) complexes with 2'-deoxyguanosine 5'-triphosphate and L-histidine. J Inorg Biochem 99:737-46
Golebiowski, Filip; Kasprzak, Kazimierz S (2005) Inhibition of core histones acetylation by carcinogenic nickel(II). Mol Cell Biochem 279:133-9

Showing the most recent 10 out of 25 publications