RESUMEN
B cell leukemia-3 (Bcl-3) has been defined as an anti-apoptotic gene; however, the exact mechanisms through which Bcl-3 influences apoptosis have been elusive. To determine the specific role of Bcl-3 in apoptosis, we evaluated the effect of its silencing on the expression of proteins involved in either the extrinsic or intrinsic apoptotic pathways induced by ultraviolet light B-mediated DNA damage. We found that, in Bcl-3-silenced cells, caspase-3, caspase-8 and caspase-9 activation is accelerated and tBid mitochondrial content is increased. It is important to note that, although mitochondrial Smac levels were reduced after UV exposure, the rate of reduction was slightly higher in Bcl-3 silenced cells than in control cells. Additionally, p53 levels diminished in Bcl-3 silenced cells compared to control cells, as did those of DNA-PK, a DNA repair protein. Altogether, our data indicate that Bcl-3 protects cells from apoptosis by regulating both apoptotic pathways.
Asunto(s)
Apoptosis/genética , Apoptosis/efectos de la radiación , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Rayos Ultravioleta/efectos adversos , Proteínas Reguladoras de la Apoptosis , Proteínas del Linfoma 3 de Células B , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Caspasas/metabolismo , Daño del ADN/efectos de la radiación , Silenciador del Gen , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Cisplatin (CDDP) is a chemotherapeutic agent that produces nephrotoxicity associated with oxidative/nitrosative stress. alpha-Mangostin (alpha-M) is a xanthone extracted from mangosteen with antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate the renoprotective effect of alpha-M on the CDDP-induced nephrotoxicity. alpha-M was administered (12.5 mg/kg/day, i.g.) for 10 days (7 days before and 3 days after CDDP injection). On day 7, rats were treated with a single injection of CDDP (7.5 mg/Kg, i.p.); 3 days after the rats were killed. alpha-M attenuated renal dysfunction, structural damage, oxidative/nitrosative stress, decrease in catalase expression and increase in mRNA levels of tumour necrosis factor alpha and transforming growth factor beta. In conclusion the renoprotective effect of alpha-M on CDDP-induced nephrotoxicity was associated with the attenuation in oxidative/nitrosative stress and inflammatory and fibrotic markers and preservation of catalase activity.
Asunto(s)
Cisplatino/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Xantonas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Antioxidantes/farmacología , Cisplatino/farmacocinética , Interacciones Farmacológicas , Enfermedades Renales/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer.
Asunto(s)
Inhibidores Tisulares de Metaloproteinasas/química , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Animales , Progresión de la Enfermedad , Regulación Enzimológica de la Expresión Génica , Humanos , Metaloproteinasas de la Matriz/metabolismo , Neoplasias/enzimología , Neoplasias/patología , Especificidad de Órganos , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
Ukrain is a reaction product of different alkaloids from Chelidonium majus L. (celandine) conjugated with thiophosphoric acid. It has immunoregulatory effects on T lymphocyte subsets and cytotoxic and cytostatic effects on various malignant cells. Although Ukrain has been reported to induce alterations in the cell cycle and tubulin polymerization, the specific cellular target has not been described. Since antineoplasic agents induce NF-kappaB and their effects are regulated by this transcription factor, we investigated its possible participation in the apoptotic effects of Ukrain. Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway, as demonstrated by the cleavage of caspase 9 and the upregulation and cleavage of caspase 3. The effect was reversible, since long exposures (24 hours or more) were needed, as verified by clonogenic assays. Gene reporter assays showed that Ukrain activated NF-kappa B. Nevertheless, this activation was not required for, and did not modulate, the Ukrain effect: neither blockage of activation by a dominant negative version of Ikappa-B alpha or a Bcl-3 siRNA, nor activation of the pathway by overexpression of IKK2, changed the response to the drug. In conclusion, Ukrain induced apoptosis in HeLa cervical cancer cells by activating the intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.