RESUMEN
Yes-associated protein 1 (YAP1) and its paralogue PDZ-binding motif (TAZ) play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29 049 low-molecular-weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS-induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT-treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS-YAP pathway driving tumor cell growth and so could be a potent anticancer drug.
Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Lactonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos de Eudesmano/farmacología , Aciltransferasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Auranofina/farmacología , Movimiento Celular , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Autorrenovación de las Células , Proteínas de Unión al ADN/metabolismo , Descubrimiento de Drogas , Femenino , Inula/química , Luciferasas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteínas Nucleares/metabolismo , Fosforilación/efectos de los fármacos , Proteolisis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Factores de Transcripción de Dominio TEA , Neoplasias de la Lengua/inducido químicamente , Neoplasias de la Lengua/prevención & control , Factores de Transcripción/metabolismo , Activación Transcripcional , Proteínas Señalizadoras YAPRESUMEN
The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Transcripción Genética , Animales , Polaridad Celular/genética , Matriz Extracelular/genética , Vía de Señalización Hippo , Humanos , Ratones , Mutación/genética , Transducción de Señal/genética , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
The Hippo signalling pathway monitors cell-cell contact and external factors that shape tissue structure. In mice, tumourigenesis and developmental abnormalities are common consequences of dysregulated Hippo signalling. Expression of Hippo pathway components is also frequently altered in human tumours and correlates with poor prognosis and reduced patient survival. Thus, the Hippo pathway is an attractive anti-cancer target. Here, we provide an overview of the function and regulation of Hippo signalling components and summarize progress to date on the development of agents able to regulate Hippo signalling for cancer therapy.