Molecular mechanisms of nickel carcinogenesis

Cangül, Hakan; Broday, Limor; Salnikow, Konstantin; Sutherland, Jessica E.; Wu, Peng; Zhang, Q.; Poltaratsky, V.; Yee, Herman; Zoroddu, M. A.; Costa, Max

doi:10.1016/s0378-4274(01)00485-4

Cited by 93 publications

(41 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Heavy metals can have a multitude of effects on the cellular homeostasis, leading to a large array of repercussions. Some of the known effects include DNA breaks, through the induction of reactive oxygen species (ROS), [42][43][44] alterations in gene expression, [45][46][47] and the enhancement of mutagenic properties of other DNA-damaging agents, such as UV light, due to the inhibition of DNA-repair enzymes. 48,49 Understanding how heavy metals influence L1 retrotransposition may be important in understanding the extent of the toxic and carcinogenic effects of heavy metals on cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

El-Sawy

Kale

Dugan

et al. 2005

Journal of Molecular Biology

View full text Add to dashboard Cite

Sequence studies of the human genome demonstrate that almost half of the DNA is derived from mobile elements. Most of the current retrotransposition activity arises from L1 and the L1-dependent, non-autonomous elements, such as Alu, contributing to a significant amount of genetic mutation and genomic instability. We present data demonstrating that nickel chloride, but not cobalt chloride, is able to stimulate L1 retrotransposition about 2.5-fold. Our data suggest that the stimulation occurs at a post-transcriptional level, possibly during the integration process. The effect of nickel on the cell is highly complex, limiting the determination of the exact mechanism of this stimulation. The observed stimulation of L1 retrotransposition is not due to a general increase in L1 transcription or an increase in the number of genomic nicks caused by nickel, but more likely caused by a decrease in DNA repair activities that influence the downstream events of retrotransposition. Our observations demonstrate the influence of environmental toxicants on human retroelement activity. We present an additional mechanism for heavy-metal carcinogenesis, where DNA damage through mobile element activation must be considered when dealing with genomic damage/instability in response to environmental agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

El-Sawy

Kale

Dugan

et al. 2005

Journal of Molecular Biology

View full text Add to dashboard Cite

show abstract

“…An important clue toward understanding the H3K9me2 domains comes from studies that investigated silencing of a transgene following the exposure of cells to nickel (13,14). Nickel compounds are environmental carcinogens that cause a multitude of human health risks including allergic dermatitis, bronchitis, pulmonary fibrosis, pulmonary edema, diseases of the kidney and cardiovascular system, and lung and nasal cancers (15,16). Despite the conclusive health risks of Ni compounds, the underlying mechanisms are not well understood because their mutagenic potential is very low and does not correlate with its potent toxicity (17).…”

mentioning

confidence: 99%

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Jose

Jagannathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Investigations into the genomic landscape of histone modifications in heterochromatic regions have revealed histone H3 lysine 9 dimethylation (H3K9me2) to be important for differentiation and maintaining cell identity. H3K9me2 is associated with gene silencing and is organized into large repressive domains that exist in close proximity to active genes, indicating the importance of maintenance of proper domain structure. Here we show that nickel, a nonmutagenic environmental carcinogen, disrupted H3K9me2 domains, resulting in the spreading of H3K9me2 into active regions, which was associated with gene silencing. We found weak CCCTC-binding factor (CTCF)-binding sites and reduced CTCF binding at the Ni-disrupted H3K9me2 domain boundaries, suggesting a loss of CTCF-mediated insulation function as a potential reason for domain disruption and spreading. We furthermore show that euchromatin islands, local regions of active chromatin within large H3K9me2 domains, can protect genes from H3K9me2-spreadingassociated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.insulator | nickel toxicity | nickel carcinogenesis

show abstract

“…Epidemiological studies have associated occupational exposure to nickel compounds to elevated incidences of human cancer such as lung and nasal cancers (4). Numerous studies from cell culture models and experimental animal models have also confirmed the carcinogenic potency of nickel compounds (4,5). Although the mechanisms implicated in the carcinogenic effect of nickel compounds are not well understood, it is accepted that the carcinogenic effects of nickel occur through alterations in cancer development-related gene expression (6).…”

mentioning

confidence: 99%

Nickel Compounds Render Anti-apoptotic Effect to Human Bronchial Epithelial Beas-2B Cells by Induction of Cyclooxygenase-2 through an IKKβ/p65-dependent and IKKα- and p50-independent Pathway

Ding

Zhang

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

The carcinogenicity of nickel compounds has been well documented both in vitro and in vivo; however, the molecular mechanisms by which nickel compounds cause cancers are far from understood. Because suppression of apoptosis is thought to contribute to carcinogenesis, we investigated the mechanisms implicated in nickel-induced anti-apoptotic effect in human bronchial epithelial (Beas-2B) cells. We found that exposure of Beas-2B cells to nickel compounds resulted in increased cyclooxygenase-2 (COX-2) expression and that small interfering RNA (siCOX-2) knockdown of COX-2 expression resulted in increased cell sensitivity to nickel-triggered cell apoptosis, demonstrating that COX-2 induction has an anti-apoptotic effect on Beas-2B cells. Overexpression of IKK␤-KM, a kinase inactive mutant of IKK␤, blocked NF-B activation and COX-2 induction by nickel compounds, indicating that activated NF-B may be a mediator for COX-2 induction. To further explore the contribution of the NF-B pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKK␤, IKK␣, p65, and p50 were analyzed. Loss of IKK␤ impaired COX-2 induction by nickel exposure, whereas knockout of IKK␣ had a marginal effect. Moreover, the NF-B p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKK␤ or p65 rendered cells more sensitive to nickel-induced apoptosis as compared with those in wild type cells. Finally, it was shown that reactive oxygen species H 2 O 2 were involved in both NF-B activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKK␤/p65 NF-B-dependent but IKK␣-and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.

show abstract

Molecular mechanisms of nickel carcinogenesis

Cited by 93 publications

References 17 publications

Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Nickel Compounds Render Anti-apoptotic Effect to Human Bronchial Epithelial Beas-2B Cells by Induction of Cyclooxygenase-2 through an IKKβ/p65-dependent and IKKα- and p50-independent Pathway

Contact Info

Product

Resources

About