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Arsenic and benzo[a]pyrene co-exposure acts synergistically in inducing cancer stem cell-like property and tumorigenesis by epigenetically down-regulating SOCS3 expression.

ABSTRACT: Arsenic and benzo[a]pyrene (BaP) are among the most common environmental carcinogens causing lung cancer. Millions of people are exposed to arsenic through consuming arsenic-contaminated drinking water. High levels of BaP are found in well-done barbecued meat and other food in addition to cigarette smoke. Hence, arsenic and BaP co-exposure in humans is common. However, the combined health effect and the underlying mechanism of arsenic and BaP co-exposure have not been well-understood. In this study we investigate the combined tumorigenic effect of arsenic and BaP co-exposure and the mechanism using both cell culture and mouse models. It was found that arsenic (sodium arsenite, 1.0 µM) and BaP (2.5 µM) co-exposure for 30 weeks synergizes in inducing malignant transformation of immortalized non-tumorigenic human bronchial epithelial cells and cancer stem cell (CSC)-like property to enhance their tumorigenicity. In animal studies, A/J mice were exposed to arsenic in drinking water (sodium arsenite, 20 ppm) starting from gestation day 18. After birth, the dams continuously received arsenic water throughout lactation. At weaning (3 weeks of age), male offspring were exposed to either arsenic alone via drinking the same arsenic water or exposed to arsenic plus BaP. BaP was administered via oral gavage (3 µmol per mouse per week) once a week starting from 3 weeks of age for 8 weeks. All mice were euthanized 34-weeks after the first BaP exposure. It was found that mice in control and arsenic exposure alone group did not develop lung tumors. All mice in BaP exposure alone group developed lung adenomas. However, arsenic and BaP co-exposure synergized in increasing lung tumor multiplicity and tumor burden. Furthermore, 30% of mice in arsenic and BaP co-exposure group also developed lung adenocarcinomas. Mechanistic studies revealed that arsenic and BaP co-exposure does not produce more BPDE-DNA adducts than BaP exposure alone; but acts synergistically in activating aryl hydrocarbon receptor (AhR) to up-regulate the expression of a histone H3 lysine 9 methyltransferase SUV39H1 and increase the level of suppressive H3 lysine 9 dimethylation (H3K9me2), which down-regulates the expression of tumor suppressive SOCS3 leading to enhanced activation of Akt and Erk1/2 to promote cell transformation, CSC-like property and tumorigenesis. Together, these findings suggest that arsenic and BaP co-exposure synergizes in causing epigenetic dysregulation to enhance cell transformation, CSC-like property and tumorigenesis.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7099608 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: MCL-1 is up-regulated in cancer and a target for cancer treatment. How MCL-1 is up-regulated and whether MCL-1 up-regulation plays a role in tumorigenic process is not well-known. Arsenic and benzo(a)pyrene (BaP) are well-recognized lung carcinogens and we recently reported that arsenic and BaP co-exposure acts synergistically in inducing cancer stem cell (CSC)-like property and lung tumorigenesis. This study was performed to further investigate the underlying mechanism focusing on the role of MCL-1. Methods: The spheroid formation assay and nude mouse tumorigenesis assay were used to determine the CSC-like property and tumorigenicity of arsenic plus BaP co-exposure-transformed human bronchial epithelial BEAS-2B cells, respectively. Biochemical, pharmacological and genetic approaches were used to manipulate gene expressions, dissect signaling pathways and determine protein-protein interactions. Both loss-of-function and gain-of-function approaches were used to validate the role of MCL-1 in arsenic plus BaP co-exposure-enhanced CSC-like property and tumorigenicity. Results: Arsenic plus BaP co-exposure-transformed cells express significantly higher protein levels of MCL-1 than the passage-matched control, arsenic or BaP exposure alone-transformed cells. Knocking down MCL-1 levels in arsenic plus BaP co-exposure-transformed cells significantly reduced their apoptosis resistance, CSC-like property and tumorigenicity in mice. Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation. Conclusions: The deubiquitinase USP7-mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC-like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.

Project description:Polycyclic aromatic hydrocarbons (PAHs) and heavy metal/loid(s) are common environmental pollutants. Toxicological interaction data on benzo[a]pyrene (B[a]P) and heavy metal/loid(s) are lacking. In this study, we have determined the combined toxicity of B[a]P, arsenic (As), cadmium (Cd) and lead (Pb) in HepG2 cells. The binary, ternary and quaternary mixture toxicity of B[a]P and heavy metal/loid(s) was predicted by using the combination index (CI)-isobologram method. This method is useful to predict the quantitative nature of an interaction between chemicals at different effect (inhibitory concentration) levels from 0.1 to 99% using computerised quantitation. A total of 11 mixtures including six binary mixtures, four ternary and one quaternary mixtures of B[a]P and heavy metal/loid(s) were evaluated for their interactions. The cytotoxicity of individual and multi-component mixtures was evaluated by MTS assay. The selected concentrations for the individual dose response study were 0-100 ?M - B[a]P; 0-40 ?M - Cd; 0-400 ?M - As and Pb. The individual dose response results showed that all four chemicals were toxic to liver cells with Cd being the most potent toxicant. Mixtures of B[a]P and heavy metal/loid(s) were prepared based on their individual Dm concentration using a 1?:?1 ratio and exposed to HepG2 cells. By using the CI-isobologram method, the predicted interactions between these chemicals were synergism, additivity or antagonism at different effect levels. All the mixtures except the ternary mixture of B[a]P + As + Pb displayed synergism at a lower effect level (IC10-IC30), and additivity, synergism or antagonism at 50-90% effect levels. Among these mixtures, mixtures of heavy metal/loid(s) (both binary and ternary combinations) and a quaternary mixture of B[a]P + As + Cd + Pb showed a strong synergistic response at lower effect levels compared to other mixtures. The predicted interaction response by the CI method was compared with classical models of concentration addition and independent action. The CI method displayed an improved prediction power compared to classical models. The predicted synergistic interaction between B[a]P and heavy metal/loid(s) may have important implications in the human health risk assessment of these mixed chemical mixtures at contaminated sites.

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Arsenic and benzo[a]pyrene co-exposure acts synergistically in inducing cancer stem cell-like property and tumorigenesis by epigenetically down-regulating SOCS3 expression.

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