Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer

Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer

Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer

Abstract Background ErbB2 overexpression identifies a subset of breast cancer as ErbB2-positive and is frequently associated with poor clinical outcomes. As a membrane-embedded receptor tyrosine kinase, cell surface levels of ErbB2 are regulated dynamically by membrane physical properties. The present study aims to investigate the influence of membrane cholesterol contents on ErbB2 status and cellular responses to its tyrosine kinase inhibitors. Methods The cholesterol abundance was examined in ErbB2-positive breast cancer cells using filipin staining. Cellular ErbB2 localizations were investigated by immunofluorescence with altered membrane cholesterol contents. The inhibitory effects of the cholesterol-lowering drug lovastatin were assessed using cell proliferation, apoptosis, immunoblotting and immunofluorescence assays. The synergistic effects of lovastatin with the ErbB2 inhibitor lapatinib were evaluated using an ErbB2-positive breast cancer xenograft mouse model. Results Membrane cholesterol contents positively correlated with cell surface distribution of ErbB2 through increasing the rigidity and decreasing the fluidity of cell membranes. Reduction in cholesterol abundance assisted the internalization and degradation of ErbB2. The cholesterol-lowering drug lovastatin significantly potentiated the inhibitory effects of ErbB2 kinase inhibitors, accompanied with enhanced ErbB2 endocytosis. Lovastatin also synergized with lapatinib to strongly suppress the in vivo growth of ErbB2-positive breast cancer xenografts. Conclusion The cell surface distribution of ErbB2 was closely regulated by membrane physical properties governed by cholesterol contents. The cholesterol-lowering medications can hence be exploited for potential combinatorial therapies with ErbB2 kinase inhibitors in the clinical treatment of ErbB2-positive breast cancer

Overcoming Hypoxia-Induced Apoptotic Resistance through Combinatorial Inhibition of GSK-3β and CDK1

Hasta ahora los diferentes modelos educativos de la enseñanza en lenguas se han venido clasificando en sistemas de opción y conjunción lingüística según posibilitasen elegir el idioma que iba a ocupar un lugar central en la enseñanza o no. Sin embargo la introducción en los planes de estudio de varias Comunidades Autónomas de lenguas extranjeras, no solo como materia de estudio sino como medio de transmisión de conocimientos, reclama la inclusión de nuevos parámetros que tengan en cuenta el número de lenguas vehiculares de la enseñanza, distinguiendo complementariamente los modelos monolingües, bilingües y plurilingües. A partir de estas variables, y utilizando la terminología de la Comisión Europea, los autores proponen una nueva sistematización de los modelos lingüísticos de las Comunidades Autónomas con lengua cooficial capaz de abarcar toda su complejidad. También señalan sus límites, de acuerdo con la jurisprudencia del Tribunal Constitucional y los tribunales ordinarios, y realizan una apuesta por el aprendizaje integrado de contenidos y lenguas (AICLE).Until the present, idiomatic models of education have distinguished between linguistical choice or conjunction, whether it was possible to choose the language which would occupy a central space at school or not. Nevertheless, the teaching of foreign languages in the educational schemes of several Spanish regional governments, not only as a subject but also as a way of study non linguistic areas, requires new patterns that include the languages in which education is offered, in particular, monolingualism, bilingualism and plurilingualism. Knowing all these varieties, and using the European Commission´s common vocabulary, the authors propose a new classification for the linguistic models held by the Spanish regional governments with two equally recognized languages. Regarding the Constitutional Court case-law and other jurisprudence, they also point the limits and advocate for content and language integrated learning (CLIL)