Certain transition metals, including nickel, chromium, cadmium, and copper, are carcinogenic to humans and/or animals. They induce cancer of the respiratory tract in persons exposed to metal-containing aerosols and also increase the incidence of childhood malignancies in progeny of the exposed fathers. However, mechanisms of the carcinogenic activity of these metals remain obscure. In recent years, we have been testing a hypothesis that the mechanisms would involve metal-mediated structural and/or oxidative damage to chromatin and some enzymatic proteins.? ? In 2004/2005 we continued investigations based on the above hypothesis. Our research on transition metals' interactions with chromatin components were focused on Ni(II)-assisted modifications of core histones, especially histone H2B. As we have found before, Ni(II) mediates hydrolytic cleavage of the C-terminal tail of histone H2A. To check biological consequences of such cleavage, we obtained constructs of the truncated and full-length histones H2A, transfected them to cells, found their integration into chromosomes, and identified gene clusters and individual genes that were expressed differently in cells bearing the truncated histone H2A. Cells cultured with Ni(II) also showed extensive modification of histone H2B, a close partner of H2A in chromatin. In addition to modifications identified before (truncation and alterations in ubiquitination and acetylation) we have discovered two novel effects of Ni(II) exposure on histone H2B, including (1) oxidation of the Met-59 and Met-61 residues and (2) deamidation of the Glu-22 residue. As we also found recently, the mechanisms of H2B truncationand deamidation are likely to involve activation by Ni(II) of two calcium dependent families of enzymes, calpains and transglutaminases, respectively. The oxidation of methionines in H2B may, in turn, result from Ni(II)-induced oxidative stress.? ? Following our search for toxic metals' effects on enzymatic proteins, we continued investigations of possible role of the tumor suppressor protein Fhit, a diadenosine triphosphate phosphohydrolase, in the mechanisms of metal-induced carcinogenesis. Since Fhit is a pro-apoptotic protein, its suppression by nickel may contribute to the survival of cells mutated by nickel and thus assist in carcinogenesis. Following our previous finding of Fhit inhibition by Ni(II) in cultured cells and mice, we studied the status of Fhit over the course of nickel-induced muscle and kidney carcinogenesis in rats and found that reduction of Fhit expression is an early and persisting effect in these two experimental models. ? ? Another investigation has been focused on the MTH1 proteins, the oxidized purine nucleoside triphosphate pyrophosphohydrolases (8-oxo-dGTPases), a class of mammalian enzymes preventing incorporation of promutagenic oxidized purine nucleotides into DNA or RNA. Our recent studies included the chemistry of Ni(II)-mediated generation of MTH1's substrate and product, 8-oxo-dGTP and 8-oxo-dGMP. The underlying reactions involve the formation of binary and ternary complexes of Ni(II) with dGTP, dGMP, and histidine that are more susceptible to oxidation than free ligands. Emergence of the resulting oxidation products, e.g., 8-oxo-dGMP, in cells, may inhibit MTH1 activity.? ? In FY2005, we continued to investigate metals' effects on yet another enzyme, HIF-1alpha prolyl hydroxylase (PH). PH is activated by Fe(II) and may therefore be sensitive to interference by the carcinogenic metals Ni(II) and Co(II) (and possibly others). This enzyme is crucial for up-regulation of the hypoxia-inducible factor HIF-1alpha that mediates cellular response to hypoxia. Our previous investigations in cultured cells showed that this effect was elicited through inhibition of PH by the metals.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC004582-30
Application #
7283969
Study Section
(LCC)
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2005
Total Cost
Indirect Cost
Name
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

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