Mechanisms of arsenic-induced cell transformation

Barrett, J. Carl; Lamb, Patricia W.; Wang, T C; Lee, T C

doi:10.1007/bf02917284

Cited by 96 publications

(54 citation statements)

References 25 publications

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“…Many possible modes of arsenic action have been proposed, including chromosomal abnormalities, oxidative stress, altered DNA repair and DNA methylation patterns, altered cell proliferation, abnormal gene amplification, and inhibition of p53 and telomerase (5,(13)(14)(15)(16)(17)(18). In particular, arsenic exerts its toxicity by generating reactive oxygen species (ROS) 1 (19 -22).…”

mentioning

confidence: 99%

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Liu

Trimarchi

Navarro

et al. 2003

Journal of Biological Chemistry

196

141

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The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an antitumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome endto-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.Arsenic is a significant environmental concern worldwide because millions of people are at risk of drinking water contaminated by arsenic (1, 2). Epidemiological data show that chronic exposure of humans to inorganic arsenic is associated with hepatic injury, peripheral neuropathy, and increased rates of a wide variety of cancers, particularly of the skin, lung, bladder, and liver (3-5). Arsenic also produces toxic effects on the female reproductive system, including ovarian dysfunction (6), aberrant embryo development and lethality (7,8), and postnatal growth retardation (9). Interestingly, it also has proven useful for anti-cancer therapy (10 -12), although the mechanisms underlying its paradoxical (antineoplastic) effects remain unclear.Many possible modes of arsenic action have been proposed, including chromosomal abnormalities, oxidative stress, altered DNA repair and DNA methylation patterns, altered cell proliferation, abnormal gene amplification, and inhibition of p53 and telomerase (5, 13-18). In particular, arsenic exerts its toxicity by generating reactive oxygen species (ROS) 1 (19 -22). Mitochondria, the main source of ROS production, which also play a crucial role in the control of apoptosis (23, 24), have been implicated in arsenite-induced apoptosis (21, 25). Thus, mitochondrial dysfunction may explain the cytotoxicity and degenerative effects induced by arsenic. How ROS links arsenic exposure to carcinogenesis is still not well understood.Vertebrate telomeres consist of tandem repeats of G-rich sequence that cap the ends of chromosomes, protecting them from fusion and chromosomal instability...

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confidence: 99%

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Liu

Trimarchi

Navarro

et al. 2003

Journal of Biological Chemistry

196

141

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“…Animal models are of little help in understanding its mechanism; for reasons that are not clear arsenic is not carcinogenic in rodent models. It is one of the few, possibly the only, well-established human carcinogen that does not induce tumors in laboratory animals (4,5).…”

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confidence: 99%

Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species

Hei

Liu²,

Waldren³

1998

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

392

251

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Arsenite, the trivalent form of arsenic present in the environment, is a known human carcinogen that lacked mutagenic activity in bacterial and standard mammalian cell mutation assays. We show herein that when evaluated in an assay (A L cell assay), in which both intragenic and multilocus mutations are detectable, that arsenite is in fact a strong dose-dependent mutagen and that it induces mostly large deletion mutations. Cotreatment of cells with the oxygen radical scavenger dimethyl sulfoxide significantly reduces the mutagenicity of arsenite. Thus, the carcinogenicity of arsenite can be explained at least in part by it being a mutagen that depends on reactive oxygen species for its activity.

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“…The intracellular iron homeostasis is maintained by the iron-mediated IRP-IRE interaction that inversely regulates ferritin and TfR [47]. When iron levels are high, an iron-sulfur cluster (4Fe-4S) forms in the core of IRP-1 and prevents IRE binding [48,49], whereas IRP2 is rapidly degraded [8,48,49]. This results in a decreased IRP-IRE interaction, leading to an increased ferritin synthesis and TfR mRNA degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies show that arsenite is a complete transplacental carcinogen in mice [6], while dimethylarsinic acid, a major metabolite of arsenic in most mammals, including humans, causes bladder cancer in F344 rats [7]. In contrast to its weak mutagenicity, arsenite induces cell transformation of various types of cells to a more malignant phenotype, such as Syrian hamster embryo cells [8], mouse embryo fibroblasts [9], mouse epidermal JB6 C141 cells [10], rat liver-derived TRL 1215 cells [11], normal human immortalized prostate epithelium RWPE-1 cells [12], as well as human osteogenic sarcoma (HOS) cells [13,14]. Many mechanisms involving arsenic-mediated cell transformation have been proposed.…”

Section: Introductionmentioning

confidence: 99%

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenitetransformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.

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Mechanisms of arsenic-induced cell transformation

Cited by 96 publications

References 25 publications

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species

Altered iron homeostasis involvement in arsenite-mediated cell transformation

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