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EMBO J ; 24(15): 2815-26, 2005 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-16001080

RESUMO

Apoptosis-inducing factor (AIF) exhibits reactive oxygen species (ROS)-generating NADH oxidase activity of unknown significance, which is dispensable for apoptosis. We knocked out the aif gene in two human colon carcinoma cell lines that displayed lower mitochondrial complex I oxidoreductase activity and produced less ROS, but showed increased sensitivity to peroxide- or drug-induced apoptosis. AIF knockout cells failed to form tumors in athymic mice or grow in soft agar. Only AIF with intact NADH oxidase activity restored complex I activity and anchorage-independent growth of aif knockout cells, and induced aif-transfected mouse NIH3T3 cells to form foci. AIF knockdown in different carcinoma cell types resulted in lower superoxide levels, enhanced apoptosis sensitivity and loss of tumorigenicity. Antioxidants sensitized AIF-expressing cells to apoptosis, but had no effect on tumorigenicity. In summary, AIF-mediated resistance to chemical stress involves ROS and probably also mitochondrial complex I. AIF maintains the transformed state of colon cancer cells through its NADH oxidase activity, by mechanisms that involve complex I function. On both counts, AIF represents a novel type of cancer drug target.


Assuntos
Apoptose/fisiologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Complexo I de Transporte de Elétrons/fisiologia , Flavoproteínas/fisiologia , Proteínas de Membrana/fisiologia , Animais , Fator de Indução de Apoptose , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Dano ao DNA , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Proteínas de Membrana/deficiência , Camundongos , Camundongos Nus , Mitocôndrias/enzimologia , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Células NIH 3T3 , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo
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