RESUMEN
p53 is essential for the cellular responses to DNA damage that help to maintain genomic stability. However, the great majority of human cancers undergo disruption of the p53-network. Identification and characterization of molecular components important in both p53-dependent and -independent apoptosis might be useful in developing novel therapies for cancers. In the complete absence of p53, cells treated with N-(phosphonacetyl)-L-aspartate (PALA) continue to synthesize DNA slowly and eventually progress through S-phase, suffering severe DNA damage that in turn triggers apoptosis, whereas cells with functional p53 undergo growth arrest. In this study, we investigated apoptotic signaling in response to PALA and the role of p53 expression in this pathway. We found that treatment of cells lacking p53 with PALA induced TAp73, Noxa and Bim and inactivation of these proteins with dominant-negative plasmids or small interfering RNAs significantly inhibited apoptosis, suggesting that PALA-induced apoptosis was mediated via TAp73-dependent expression of Noxa and Bim. However, PALA treatment inhibited the expression of ΔNp73 only in cells lacking p53 but not in cells expressing p53. In addition, PALA treatment inhibited Bcl-2, and overexpression of Bcl-2 significantly inhibited PALA-induced apoptosis. Moreover, expression of p53 in these cells protected them from PALA-induced apoptosis by activating p21, sustaining the expression of ΔNp73 and inhibiting the induction of Noxa and Bim. Taken together, our study identifies novel but opposing roles for the p53 and TAp73 in the induction of Noxa and Bim and regulation of apoptosis. Our data will help to develop strategies to eliminate cancer cells lacking p53 while protecting normal cells with wild-type p53.
Asunto(s)
Apoptosis/efectos de los fármacos , Ácido Aspártico/análogos & derivados , Proteínas de Unión al ADN/fisiología , Neoplasias/tratamiento farmacológico , Proteínas Nucleares/fisiología , Ácido Fosfonoacético/análogos & derivados , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Supresoras de Tumor/fisiología , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ácido Aspártico/farmacología , Ácido Aspártico/uso terapéutico , Proteína 11 Similar a Bcl2 , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ácido Fosfonoacético/farmacología , Ácido Fosfonoacético/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Botanical and nutritional compounds have been used for the treatment of cancer throughout history. These compounds also may be useful in the prevention of cancer. Population studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals, including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants. Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action.