Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling.
We have summarized the molecular and cellular events involved in nickel (Ni) compound induced carcinogenesis. The major hypothesis for nickel carcinogenic action has involved the ability of the Ni compound to deliver high concentrations of Ni intracellularly, enter the nucleus and interact with chromatin. Ni has been found to selectively damage heterochromatin, and a major action of Ni is its ability to silence the expression of genes located near heterochromatin by inducing a loss of histone H4 and H3 acetylation and DNA hypermethylation. When Ni silences critical genes, such as tumor suppressor genes, the cell is altered to a greater state of neoplastic transformation. The carcinogenic hazard of Ni compounds has been directly related to the ability of that Ni compound to raise the intracellular Ni ions. The mechanisms of Ni-induced gene silencing will be discussed. However, recently it has been found that soluble Ni ions can interact with the cell surface receptors and activate cell signaling resulting in the induction of a variety of cellular genes. In particular, the Ca and hypoxia inducible factor pathway is activated in all cells exposed to soluble Ni ions. In the case of HIF-1 induction, a cell is now equipped with the expression of a variety of genes that will allow the cell to survive the lack of oxygen and thus should enable a previously initiated cancer cell to progress into a full malignant state and metastasize. These new findings support the view that soluble Ni ions exhibit carcinogenic potential by activating cell promotion and lend strength to the epidemiological data showing soluble Ni to be associated with cancer risk in Ni refinery workers.
Costa
Max
M
Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. costam@env.med.nyu.edu
Yan
Yan
Y
Zhao
Daoji
D
Salnikow
Konstantin
K
D020013:Calcium Signaling; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000209:etiology / Q000503:physiopathology; D009532:Nickel / Q000009:adverse effects*; D009687:Nuclear Proteins / Q000187:drug effects; D018570:Risk Assessment; D015398:Signal Transduction; D014157:Transcription Factors
D002843:Chromatin; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D009532:Nickel