| Arsenic is one of ubiquitous submetallic elements that exist in both nature and occupational place. Epidemical research has revealed that long-term exposing to arsenic can cause not only acute and chronic arsenic poisoning, but also induce cancer, mutation and teratogenicity. Arsenic has been classified as a group 1 carcinogen for humans by International Agency for Research on Cancer (IARC). A number of evidences have shown that arsenic is of property to promote tumor by inducing intracellular signal transduction, activating transcription factors and changing the expression of genes that are involved in promoting cell growth, proliferation and malignant transformation. Activator protein-1 (AP-1) is one of the most important transcription factors working as a central of many different intranuclear signal transduction pathways, and it binds to DNA at the promoter regions of a number of genes controlling cell proliferation, apoptosis, and transformation. As one of the mechanisms of arsenic carcinogenesis, oxidative stress has been accepted generally. Activation of AP-1 by oxidative stress induced by arsenic directly or indirectly may lead to alterations in the expression of genes involved in cell proliferation and transformation, favoring the development of carcinogenesis.In the regions of endemic arsenic poisoning, some researchers found that selenium concentrations in blood of residents were lower than those in normal control regions. Selenium is an essential trace element and has many biological functions, especially in preventing cancer, such as lung cancer, carcinoma of prostate and liver cancer etc. The most important and known biological effect of selenium is its anti-oxidative effect. Selenium, as an antioxidant, can eliminate free radicals and peroxidated lipid that formed in the metabolism through constructing selenoenzyme and none-enzyme selenium-compound. In addition, selenium could also inhibit AP-1 DNA binding activity in vitro by combining with the conserved cysteine residues in the DNA-binding domains of Jun and Fos.On these grounds we assume that arsenic-induced oxidative stress can active AP-1 which plays key effect in carcinogenesis, and selenium is both antioxidant and AP-1 inhibitor, then whether selenium can repress arsenic'carcinogenesis by affecting AP-1 activity induced by arsenic. Hence, we carried out this research.We chose the mouse epidermis JB6 cell as the target cell, took arsenious acid and sodium selenite as test objects, and used sodium chloride as the solvent control. We exposed JB6 cells to arsenious acid at the concentrations of 3.125, 6.25 and 12.5μmol/L or/ and to sodium selenite at the concentrations of 2.5μmol/L alone or together. AP-1 DNA binding activity and cell cycle were analyzed by EMSA and flow cytometry respectively.Meanwhile, curcumin (20μmol/L), a specific inhibitor of AP-1, was used to treat JB6 cells together with arsenious acid (12.5μmol/L) in order to explore the relation between AP-1 activity and cell cycle, to elucidate the antagonistic mechanism of selenium on arsenic's carcinogensis, and to provide scientific evidences for AP-1 using as molecular target of tumor for clinical therapy and arseniasis。The results showed that: (1) Arsenious acid (3.125, 6.25 and 12.5μmol/L) could significantly up-regulate AP-1 DNA binding activity and reduce G1 phase cells (P<0.01, P<0.01), and higher concentrations of arsenious acid (6.25 and 12.5μmol/L) increased G2 phase cells, compared with solvent control group. Sodium selenite (2.5μmol/L) showed no effect on AP-1 DNA binding activity and cell cycle. (2) Compared with corresponding concentrations of arsenious acid, co-exposure of JB6 cells to sodium selenite (2.5μmol/L) and arsenious acid (3.125, 6.25 and 12.5μmol/L) down-regulated AP-1 DNA binding activity (P<0.01), increased G1 phase cells (P<0.01), and decreased G2 phase cells (P<0.05). (3) Co-exposure of JB6 cells to curcumin and arsenious acid could significantly increased G1 phase cells and decreased G2 phase cells compared with corresponding concentrations of arsenious acid (P<0.01, P<0.01).In conclusion, arsenic could active AP-1 and induce cell cycle change which can be repressed by special AP-1inhibitor curcumin. This revealed that arsenic may change cell cycle by activating AP-1 signal pathway. Certain concentration of selenium can down-regulate arsenic-induced AP-1 DNA binding activity, which may be one of the mechanisms that selenium is of antagonistic ability against arsenic's carcinogenesis.
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