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1.
Sci Adv ; 3(11): eaao1193, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29134198

RESUMEN

Mammalian cells produce hundreds of dynamically regulated lipid species that are actively turned over and trafficked to produce functional membranes. These lipid repertoires are susceptible to perturbations from dietary sources, with potentially profound physiological consequences. However, neither the lipid repertoires of various cellular membranes, their modulation by dietary fats, nor their effects on cellular phenotypes have been widely explored. We report that differentiation of human mesenchymal stem cells (MSCs) into osteoblasts or adipocytes results in extensive remodeling of the plasma membrane (PM), producing cell-specific membrane compositions and biophysical properties. The distinct features of osteoblast PMs enabled rational engineering of membrane phenotypes to modulate differentiation in MSCs. Specifically, supplementation with docosahexaenoic acid (DHA), a lipid component characteristic of osteoblast membranes, induced broad lipidomic remodeling in MSCs that reproduced compositional and structural aspects of the osteoblastic PM phenotype. The PM changes induced by DHA supplementation potentiated osteogenic differentiation of MSCs concurrent with enhanced Akt activation at the PM. These observations prompt a model wherein the DHA-induced lipidome leads to more stable membrane microdomains, which serve to increase Akt activity and thereby enhance osteogenic differentiation. More broadly, our investigations suggest a general mechanism by which dietary fats affect cellular physiology through remodeling of membrane lipidomes, biophysical properties, and signaling.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Osteogénesis/efectos de los fármacos , Células de la Médula Ósea/citología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Cromatografía Líquida de Alta Presión , Ácidos Docosahexaenoicos/farmacología , Humanos , Lípidos/análisis , Microdominios de Membrana/efectos de los fármacos , Microdominios de Membrana/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Fenotipo , Fosforilación/efectos de los fármacos , Análisis de Componente Principal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Espectrometría de Masa por Ionización de Electrospray
2.
Mol Cancer Res ; 7(2): 210-20, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19208743

RESUMEN

Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Paclitaxel/uso terapéutico , Factor de Transcripción YY1/genética , Sitios de Unión , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Hibridación Genómica Comparativa , Docetaxel , Factores de Transcripción E2F/genética , Factores de Transcripción E2F/metabolismo , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/mortalidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/mortalidad , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Taxoides/uso terapéutico , Cicatrización de Heridas , Factor de Transcripción YY1/antagonistas & inhibidores
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