Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease.

The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.

Regulation of Epithelial-Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer.

The epithelial-mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer.

Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability.

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90.

Tratamiento del carcinoma de mama en tejido mamario ectópico axilar / Management of breast carcinoma in ectopic axillary breast tissue

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Seguridad pre-clínica y actividad biológica de Aphyllocladus spartioides weddell en procesos gingivoperiodontales / Seguridad pre-clínica y actividad biológica de Aphyllocladus spartioides weddell en procesos gingivoperiodontales

Las enfermedades gingivoperiodontales son procesos patológicos que alteran las estructuras de la encía y estructuras dentarias. El factor etiológico principal es la biopelícula de placa dental que se forma en las inmediaciones del surco gingival, cuando se desarrolla una gingivitis o una periodontitis en realidad lo que se produce es un desequilibrio entre la capacidad agresiva de los microorganismos y los mecanismos de defensa del hospedero; por tanto es una enfermedad silenciosa de gran porcentaje de morbilidad en el mundo y en nuestro país que provoca infecciones severas, perdidas dentarias e inclusive enfermedades sistémicas como la endocarditis bacteriana. En el presente trabajo se estudió el extracto acuoso de Aphyllocladus spartioides weddell el cual tiene amplio uso por la medicina tradicional de nuestro país; trabajando en sistemas de cultivos in vitro,en líneas celulares continuas y primaria determinando la Concentración citotóxica media (CC50) esta evaluación se llevo a cabo por el método de Exclusión del colorante Azul tripán y de reducción de la sal de Tetrazolium (MTT) , donde el promedio de ambos ensayos presento una (CC50) de 0.1228 mg/mL también se realizo el estudio de toxicidad local in vivo en mucosa oral de animales de experimentación (conejos), evaluando los diferentes parámetros de la mucosa oral : linfocitos, eosinofilos, vasos congestivos, hiperplasia, queratinización, numero de capas de la mucosa en diferentes estratos , no se encontraron alteraciones significativas en la mucosa , sino un posible efecto de reepitelización a nivel del estrato intermedio de la mucosa, observando un aumento de mitosis. Por ultimo se evaluó el efecto terapéutico del enjugue bucal (Retamox al 0.03g/100mL), mediante el estudio clínico con 30 pacientes que cursaban gingivitis y periodontitis, realizando el estudio microbiológico y clínico de los signos gingivoperiodontal. El estudio clínico reporto una visible disminución de bacterias patógenas como: las Fusobacterias, Espiroquetas y Streptococcus mutans spp cambios en algunos signos gingivoperiodontales relacionados con la inflamación e infección como el cambio de color, perdida de textura, disminución de las bolsas gingivales, con estos resultados obtenidos de pude decir que es una alternativa fitoterapéutica en el tratamiento de enfermedades periodontales. (AU)