Arsenite Is a Cocarcinogen with Solar Ultraviolet Radiation for Mouse Skin: An Animal Model for Arsenic Carcinogenesis

Rossman, Toby G.; Uddin, Ahmed; Burns, Fredric J.; Bosland, Maarten C.

doi:10.1006/taap.2001.9277

Cited by 207 publications

(166 citation statements)

References 39 publications

(45 reference statements)

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“…The decrease of Nrf2 activation in response to high levels of oxidative stressors observed in As-TM cells, coupled with their acquired apoptotic resistance might increase the likelihood to acquire heritable oxidative DNA damage [7,9]. This may help explain the remarkable co-carcinogenic effects of arsenic and UV irradiation observed in mouse models of dermal carcinogenesis but the absence of activity for arsenic alone [3,4]. Our previous study indicated that exogenous GSH might markedly suppress hypochlorous acid-induced Nrf2 activation in mouse macrophages [50], suggesting the enhanced GSH levels in As-TM cells might be a critical factor for the weakened Nrf2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Arsenic is also carcinogenic in rodent models, producing liver, lung, ovary and adrenal tumors after transplacental exposure [2] and skin tumors in combination with ultraviolet (UV) irradiation or phorbol esters in mice [3,4]. However, arsenic alone does not appear to induce skin cancer in these mouse models [2][3][4], suggesting events associated with arsenic-induced dermal carcinogenesis may be distinct from other target tissues. Accumulating evidence suggests that oxidative stress occurs in response to arsenic exposure [5,6] and may be one factor in dermal arsenic carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

160

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

160

147

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“…Possible mechanisms of carcinogenesis include genetic instability resulting from inhibition of telomerase transcription (35) or by acting as a cocarcinogen to inhibit DNA repair (36). Exposure to arsenic in drinking water is associated with increased risk of multiple cancers.…”

Section: Discussionmentioning

confidence: 99%

Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9

Liu

Shen

Carbrey

et al. 2002

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

459

298

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Much is known about the transport of arsenite and antimonite into microbes, but the identities of mammalian transport proteins are unknown. The Saccharomyces cerevisiae FPS1 gene encodes a membrane protein homologous to the bacterial aquaglyceroporin GlpF and to mammalian aquaglyceroporins AQP7 and AQP9. Fps1p mediates glycerol uptake and glycerol efflux in response to hypoosmotic shock. Fps1p has been shown to facilitate uptake of the metalloids arsenite and antimonite, and the Escherichia coli homolog, GlpF, facilitates the uptake and sensitivity to metalloid salts. In this study, the ability of mammalian aquaglyceroporins AQP7 and AQP9 to substitute for the yeast Fps1p was examined. The fps1⌬ strain of S. cerevisiae exhibits increased tolerance to arsenite and antimonite compared to a wild-type strain. Introduction of a plasmid containing AQP9 reverses the metalloid tolerance of the deletion strain. AQP7 was not expressed in yeast. The fps1⌬ cells exhibit reduced transport of 73 As(III) or 125 Sb(III), but uptake is enhanced by expression of AQP9. Xenopus laevis oocytes microinjected with either AQP7 or AQP9 cRNA exhibited increased transport of 73 As(III). These results suggest that AQP9 and AQP7 may be a major routes of arsenite uptake into mammalian cells, an observation potentially of large importance for understanding the action of arsenite as a human toxin and carcinogen, as well as its efficacy as a chemotherapeutic agent for acute promyelocytic leukemia.Fps1p ͉ GlpF ͉ acute promyelocytic leukemia

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“…MAPKs (14), MSK1 (18), and RSK2 (28) are involved in mediation of histone H3 phosphorylation. Arsenite acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling (29), but the relationship between arsenite and histone H3 has not reported until now. We hypothesized that arsenite could act to induce phosphorylation of histone H3 through MAPKs or other factors.…”

Section: Discussionmentioning

confidence: 99%

Arsenite-induced Phosphorylation of Histone H3 at Serine 10 Is Mediated by Akt1, Extracellular Signal-regulated Kinase 2, and p90 Ribosomal S6 Kinase 2 but Not Mitogen- and Stress-activated Protein Kinase 1

Liu

et al. 2003

Journal of Biological Chemistry

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Arsenite is known to be an environmental human carcinogen. However, the mechanism of action of this compound in skin carcinogenesis is not completely clear. Here, we provide evidence that arsenite can induce phosphorylation of histone H3 at serine 10 in a time-and dose-dependent manner in JB6 Cl 41 cells. Arsenite induces phosphorylation of Akt1 at serine 473 and increases Akt1 activity. A dominant-negative mutant of Akt1 inhibits the arsenite-induced phosphorylation of histone H3 at serine 10. Additionally, active Akt1 kinase strongly phosphorylates histone H3 at serine 10 in vitro. The arsenite-induced phosphorylation of histone H3 at serine 10 was almost completely blocked by a dominantnegative mutant of extracellular signal-regulated kinase 2 and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059. N-or C-terminal mutant mitogen-and stress-activated protein kinase 1 or its inhibitor H89 had no effect on arsenite-induced phosphorylation of histone H3 at serine 10 in JB6 Cl 41 cells. However, cells deficient in p90 ribosomal S6 kinase 2 (Rsk2 ؊/؊ ) totally block this phosphorylation in a dose-and time-dependent manner. Taken together, these results suggested that arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2 and p90 ribosomal S6 kinase 2 but not mitogen-and stress-activated protein kinase 1.

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Arsenite Is a Cocarcinogen with Solar Ultraviolet Radiation for Mouse Skin: An Animal Model for Arsenic Carcinogenesis

Cited by 207 publications

References 39 publications

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9

Arsenite-induced Phosphorylation of Histone H3 at Serine 10 Is Mediated by Akt1, Extracellular Signal-regulated Kinase 2, and p90 Ribosomal S6 Kinase 2 but Not Mitogen- and Stress-activated Protein Kinase 1

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