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1.
Molecules ; 24(17)2019 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-31461933

RESUMEN

In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.


Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Proteínas de Ciclo Celular/genética , Flavonoides/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Represoras/genética , Sophora/química , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Fosforilación , Regiones Promotoras Genéticas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , eIF-2 Quinasa/genética
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