RESUMO
BACKGROUND: Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. RESULTS: We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of ß-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac. CONCLUSIONS: The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.
Assuntos
Proteína da Polipose Adenomatosa do Colo/fisiologia , Anti-Inflamatórios não Esteroides/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Neoplasias Intestinais/prevenção & controle , Selênio/farmacologia , Sulindaco/farmacologia , Animais , Western Blotting , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Masculino , Camundongos , Camundongos Knockout , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Selenium-binding protein (SBP) 1 is present in reduced levels in several cancer types as compared with normal tissues, and lower levels are associated with poor clinical prognosis. Another selenium-containing protein, glutathione peroxidase 1 (GPX1), has been associated with cancer risk and development. The interaction between these representatives of different classes of selenoproteins was investigated. Increasing SBP1 levels in either human colorectal or breast cancer cells by transfection of an expression construct resulted in the reduction of GPX1 enzyme activity. Increased expression of GPX1 in the same cell types resulted in the transcriptional and translational repression of SBP1, as evidenced by the reduction of SBP1 messenger RNA and protein and the inhibition of transcription measured using an SBP1 reporter construct. The opposing effects of SBP1 and GPX1 on each other were also observed when GPX1 was increased by supplementing the media of these tissue culture cells with selenium, and the effect of selenium on SBP1 was shown to be GPX1 dependent. Decreasing or increasing GPX1 levels in colonic epithelial cells of mice fed a selenium-deficient, -adequate or -supplemented diet resulted in the opposing effect on SBP1 levels. These data are explained in part by the demonstration that SBP1 and GPX1 form a physical association, as determined by coimmunoprecipitation and fluorescence resonance energy transfer assay. The results presented establish an interaction between two distinct selenium-containing proteins that may enhance the understanding of the mechanisms by which selenium and selenoproteins affect carcinogenesis in humans.