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1.
Mol Cell Proteomics ; 19(2): 375-389, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31879272

RESUMEN

The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics analysis of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor-/cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT, and MAPK/ERK pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and increased epithelial-mesenchymal plasticity. In addition, the radioresistant cells exhibited enhanced capabilities of DNA repair and antioxidant defense compared with the parental cells. We focused functional analysis on one of the most up-regulated proteins in the radioresistant cells, ecto-5'-nucleotidase (CD73), which is a cell surface protein that is overexpressed in different types of cancer. Ectopic overexpression of CD73 in the parental cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 re-sensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies demonstrate that CD73 up-regulation promotes Ser-136 phosphorylation of the proapoptotic protein BAD and is required for maintaining the radioresistant cells in a mesenchymal state. Our findings suggest that expression alterations in the IR-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity and enhancement of DNA repair. Our results also suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state.


Asunto(s)
5'-Nucleotidasa/metabolismo , Neoplasias Pancreáticas/metabolismo , Tolerancia a Radiación , Radiación Ionizante , Proteína Letal Asociada a bcl/metabolismo , 5'-Nucleotidasa/genética , Línea Celular Tumoral , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Fosforilación , Regulación hacia Arriba
2.
Brain Sci ; 10(2)2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-32013124

RESUMEN

Nearly one-third of the population reports new onset or acute insomnia in a given year. Similarly, it is estimated that approximately 10% of the population endorses sleep initiation and maintenance problems consistent with diagnostic criteria for chronic insomnia. For decades, acute and chronic insomnia have been considered variations of the same condition or disorder, only really differentiated in terms of chronicity of symptoms (days/weeks versus months). Whether or not acute and chronic insomnia are part of the same phenomena is an important question, one that has yet to be empirically evaluated. The goal of the present theoretical review was to summarize the definitions of acute and chronic insomnia and discuss the role that hyperarousal may have in explaining how the pathophysiology of acute and chronic insomnia is likely different (i.e., what biopsychological factors precipitate and/or perpetuate acute insomnia, chronic insomnia, or both?).

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