RESUMEN
Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM-ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK(+) tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK(+) cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK(-) ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM-ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.
Asunto(s)
Apoptosis , Proteínas del Choque Térmico HSP72/metabolismo , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patología , Mitocondrias/patología , Proteínas Nucleares/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Proliferación Celular , Niño , Regulación hacia Abajo , Perfilación de la Expresión Génica , Proteínas del Choque Térmico HSP72/genética , Humanos , Técnicas para Inmunoenzimas , Proteínas Nucleares/genética , Nucleofosmina , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Tirosina Quinasas Receptoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Análisis de Matrices TisularesAsunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ácidos Borónicos/farmacología , Ciclo Celular/efectos de los fármacos , Linfoma de Células B Grandes Difuso/patología , Inhibidores de Proteasoma , Pirazinas/farmacología , Bortezomib , División Celular/genética , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Fase G2/efectos de los fármacos , Humanos , Complejo de la Endopetidasa ProteasomalRESUMEN
A method for positioning the cardiac end of a ventriculoatrial shunt with the aid of echocardiography is described. This simple procedure has resulted in safe and accurate shunt placement in infants.