Genotoxic Chemical Carcinogens Target Inducible Genes <i>in Vivo</i><sup>a</sup>

Hamilton, Joshua W.; McCaffrey, Jennifer; Caron, Rosemary M.; Louis, Claudine A.; Treadwell, Melinda D.; Hunt, Steven R.; Reed, Michael J.; Doherty, Kristen A.

doi:10.1111/j.1749-6632.1994.tb52846.x

Cited by 7 publications

(11 citation statements)

References 3 publications

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“…However, recent studies have demonstrated that genotoxic ( i.e. , DNA damaging) agents, including many important cancer chemotherapy drugs, can have significant and selective effects on the expression of certain inducible genes [38]. It has also been demonstrated that noncytotoxic doses of the DNA cross-linking cancer chemotherapy drugs MMC, cisplatin, and carboplatin were effective at significantly altering the expression of the MDR1 gene coding for the multidrug resistance protein P-glycoprotein [37].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

et al. 2011

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BackgroundThe cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma.MethodsWe investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo.ResultsReal-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients' biopsy specimens. In addition, EGR1 was up-regulated both in osteosarcoma patient' specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted down-regulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels.ConclusionsThese findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods.

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Section: Discussionmentioning

confidence: 99%

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

et al. 2011

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“…This same general phenomenon, i.e., preferential effects on inducible genes and correlation with DNA damage and repair, has also been observed in this system with a large number of other genotoxic and carcinogenic agents. These include the cross-linking agents cisplatin (11), and MMC (35) (11); and several synthetic acridine-based mono-and bis-intercalating agents (42). The results of many of these studies have recently been summarized (11).…”

Section: Discussionmentioning

confidence: 99%

“…These include the cross-linking agents cisplatin (11), and MMC (35) (11); and several synthetic acridine-based mono-and bis-intercalating agents (42). The results of many of these studies have recently been summarized (11). The preferential effects of each of these agents strongly correlated with DNA damage, which supports the general hypothesis that alterations in gene expression can be used as a marker for DNA damage in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Like many organic carcinogens such as benzo [a]pyrene and aflatoxin B1, chromium(VI) appears to act as a classic initiator in these test systems, and this is believed to be the principal mechanism by which chromium(VI) increases carcinogenic risk. Our laboratory has hypothesized that genotoxic carcinogens, including chromium(VI), exert preferential effects on the expression of a specific dass of genes, i.e., inducible genes, as a result of nonrandom DNA damage targeted to members of this gene class (8)(9)(10)(11)(12). Previous studies in our laboratory have shown that a number of different genotoxic chemical carcinogens that induce different types of DNA damage, including the genotoxic metals chromium and nickel, significantly alter both basal and inducible expression of several model inducible genes but have no effect on expression of constitutive genes.…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Hamilton

Kaltreider

Bajenova

et al. 1998

Environ Health Perspect

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Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic genotoxic and mutagenic agent, and DNANchromatin appears to be the principal target for its effects. In contrast, arsenic(lll) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium(VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(lll) and chromium(V1) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H411E cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(lll) and chromium(Vl) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(V1) and arsenic(lil) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure. Environ Health Perspect 1 06(Suppl 4):1 005-1015 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl4/ 1005-1015hamilton/abstract.html

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“…For example, a recent study demonstrated that "hotspots" for mutation within the P53 gene are a result, at least in large part, of preferential adduct formation at those sites (3). Previous studies in our laboratory have demonstrated that genotoxic chemical carcinogens preferentially alter expression of inducible genes in vivo at doses that are not overtly toxic to the animal (4)(5)(6)(7)(8). These effects were principally a result of transcriptional changes in the targeted genes and were closely correlated with formation of DNA damage by each agent.…”

Section: Introductionmentioning

confidence: 99%

Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene

Caron

Hamilton

1998

J. Biochem. Mol. Toxicol.

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Previous studies in our laboratory have demonstrated that genotoxic chemical carcinogens have strong preferential effects on expression of certain inducible genes at nonovertly toxic doses in vivo.The effects of the DNA cross-linking agent and chemotherapy drug, mitomycin C (MMC), on expression of the developmental and hormone-regulated gene, phosphoenolpyruvate carboxykinase (PEPCK), were examined in chick embryo liver in vivo as a function of development and were compared with changes in the chromatin structure of the PEPCK gene promoter. The liver PEPCK gene was fully hormone inducible as early as 8 days of embryonic development but was refractory to MMC until after day 10. This onset of responsiveness to MMC was correlated with qualitative changes in the pattern of DNase I hypersensitive sites (DHS) within the PEPCK promoter. There was also a gradual decrease and then a complete loss of both hormone inducibility and MMC responsiveness between 14 and 17 days of development that was correlated with a quantitative change in the overall DNase sensitivity of the liver PEPCK gene promoter over this period. These results suggest that carcinogen sensitivity of the PEPCK gene is related to its ability to respond to its normal induction signals and that chromatin structure may play a central role in these effects.

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Genotoxic Chemical Carcinogens Target Inducible Genes in Vivo^a

Cited by 7 publications

References 3 publications

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene

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Genotoxic Chemical Carcinogens Target Inducible Genes in Vivoa

Cited by 7 publications

References 3 publications

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Developmentally specific effects of the DNA cross-linking agent mitomycin C on phosphoenolpyruvate carboxykinase gene expression in vivo: Correlation with changes in chromatin structure within the promoter region of the gene

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Genotoxic Chemical Carcinogens Target Inducible Genes in Vivo^a