Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 04/2012; 262(1):11-21. DOI: 10.1016/j.taap.2012.04.014
Source: PubMed


Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway.

Download full-text


Available from: Xianglin Shi
  • Source
    • "Although CRC is not considered a hormone-dependent cancer, animal experiments showed estrogen induction of CRC (Zhang et al., 2010). Few studies reported the accumulation of ROS promoted CRC progression (Wang et al., 2012; Yang et al., 2013). Taken together, these findings suggest that DDT might induce CRC by ER and ROSmediated pathways. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dichlorodiphenyltrichloroethane (DDT), an organochlorine pollutant, is associated with several types of cancer. However, the relationship between DDT and colorectal cancer is uncertain. In this study, the impact of p,p'-DDT on colorectal cancer growth was evaluated using both in vitro and in vivo models. Our results indicated that the proliferation of human colorectal adenocarcinoma DLD1 cells was significantly promoted after exposed to low concentrations of p,p'-DDT ranging from 10(-12) to 10(-7)M for 96h. Exposure to p,p'-DDT from 10(-10) to 10(-8)M led to upregulation of phospho-GSK3β (Ser9), β-catenin, c-Myc and cyclin D1 in DLD1 cells. Rna interference of β-catenin inhibited the proliferation of DLD1 cells stimulated by p,p'-DDT. Inhibiting of estrogen receptors (ERs) had no significant effect on the action of p,p'-DDT. Treatment with p,p'-DDT induced production of intracellular reactive oxygen species (ROS) and inhibited superoxide dismutase (SOD) activity in DLD1 cells. Treatment with N-acetyl-L-cysteine (NAC), a ROS inhibitor, suppressed the induction of Wnt/β-catenin signaling and DLD1 cell proliferation by p,p'-DDT. Moreover, in a mouse xenograft model, 5nmol/kg p,p'-DDT resulted in increased tumor size, oxidative stress and Wnt/β-catenin signaling. These results indicated that low concentrations of p,p'-DDT promoted colorectal cancer growth through Wnt/β-catenin signaling, which was mediated by oxidative stress. The finding suggests an association between low concentrations of p,p'-DDT exposure and colorectal cancer progression.
    Full-text · Article · Jun 2014 · Toxicology Letters
  • Source
    • "A number of reports revealed that inorganic arsenic, especially the trivalent arsenic (As 3+ ), may induce excessive generation of the reactive oxygen species (ROS) in mammalian cells (Chou et al., 2004; Hei et al., 1998; Wang et al., 2013; Zhang et al., 2011). ROS were able to cause genetic mutation and cancer through the mechanism of DNA damage, activation of the oncogenic kinases(Wang et al., 2012), or oxidation of the important lipids and proteins to inactivate DNA repairing machineries , such as poly(ADP ribose) polymerase (PARP)-1 (Hubaux et al., 2012; Wang et al., 2013). There are several cellular sources of ROS induced by As 3+ . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our previous studies suggested that arsenic is able to induce serine 21 phosphorylation of the EZH2 protein through activation of JNK, STAT3 and Akt signaling pathways in the bronchial epithelial cell line, BEAS-2B. In the present report, we further demonstrated that reactive oxygen species (ROS) were involved in the arsenic-induced protein kinase activation that leads to EZH2 phosphorylation. Several lines of evidence supported this notion. First, pre-treatment of the cells with N-acetyl-L-cysteine (NAC), a potent antioxidant, abolishes arsenic-induced EZH2 phosphorylation along with the inhibition of JNK, STAT3 and Akt. Second, H2O2, the most important form of ROS in the cells in response to extracellular stress signals, can induce phosphorylation of the EZH2 protein and the activation of JNK, STAT3 and Akt. By ectopic expression of the myc-tagged EZH2, we additionally identified direct interaction and phosphorylation of the EZH2 protein by Akt in response to arsenic and H2O2. Furthermore, both arsenic and H2O2 were able to induce the translocation of ectopically expressed or endogenous EZH2 from nucleus to cytoplasm. In summary, the data presented in this report indicate that oxidative stress due to ROS generation plays an important role in the arsenic-induced EZH2 phosphorylation.
    Full-text · Article · May 2014 · Toxicology and Applied Pharmacology
  • Source
    • "The levels of superoxide (O2−) and peroxide (H2O2) were measured in larval hemocytes using dihydroethidium (DHE; Invitrogen, USA) and 2′, 7′-dihydrofluorescein diacetate (H2DCFDA) respectively following the methods reported earlier [9], [25] with minor modifications. Briefly, isolated hemocytes were incubated with respective dyes at the final concentration of 10 µM for 1 h in dark at 24±1°C. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The evolutionarily conserved innate immune system plays critical role for maintaining the health of an organism. However, a number of environmental chemicals including metals are known to exert adverse effects on immune system. The present study assessed the in vivo effect of a major environmental chemical, Cr(VI), on cellular immune response using Drosophila melanogaster and subsequently the protective role of superoxide dismutase (SOD) based on the comparable performance of the tested anti-oxidant enzymes. The immuno-modulatory potential of Cr(VI) was demonstrated by observing a significant reduction in the total hemocyte count along with impaired phagocytic activity in exposed organism. Concurrently, a significant increase in the percentage of Annexin V-FITC positive cells, activation of DEVDase activity, generation of free radical species along with inhibition of anti-oxidant enzyme activities was observed in the hemocytes of exposed organism. In addition, we have shown that ONOO(-) is primarily responsible for Cr(VI) induced adverse effects on Drosophila hemocytes along with O2 (-). While generation of O2 (-)/ONOO(-) in Cr(VI) exposed Drosophila hemocytes was found to be responsible for the suppression of Drosophila cellular immune response, Cr(VI) induced alteration was significantly reduced by the over-expression of sod in Drosophila hemocytes. Overall, our results suggest that manipulation of one of the anti-oxidant genes, sod, benefits the organism from Cr(VI) induced alteration in cellular immunity. Further, this study demonstrates the applicability of D. melanogaster to examine the possible effects of environmental chemicals on innate immunity which can be extrapolated to higher organisms due to evolutionary conservation of innate immune system between Drosophila and mammals.
    Full-text · Article · Feb 2014 · PLoS ONE
Show more