RESUMEN
Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.
Asunto(s)
Colesterol , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , MicroARNs , Neoplasias de la Próstata , Escualeno-Monooxigenasa , Anciano , Anciano de 80 o más Años , Animales , Humanos , Masculino , Ratones , Persona de Mediana Edad , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular , Colesterol/biosíntesis , Estudios de Cohortes , Simulación por Computador , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/genética , Ratones SCID , MicroARNs/genética , MicroARNs/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Escualeno-Monooxigenasa/antagonistas & inhibidores , Escualeno-Monooxigenasa/genética , Escualeno-Monooxigenasa/metabolismo , Terbinafina/farmacología , Activación Transcripcional/genéticaAsunto(s)
Adenocarcinoma , Autofagia , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , HumanosRESUMEN
Multidrug resistance is a major barrier against successful chemotherapy, and this has been shown in vitro to be often caused by ATP-binding cassette (ABC) transporters. These transporters are frequently overexpressed in human cancers and confer an adverse prognosis in many common malignancies. The genetic factors, however, that initiate their expression in cancer are largely unknown. Here we report that the major multidrug transporter ABCG2 (BCRP/MXR) is directly and specifically activated by the transcription factor E2F1--a factor perturbed in the majority of human cancers. E2F1 regulates ABCG2 expression in multiple cell systems, and, importantly, we have identified a significant correlation between elevated E2F1 and ABCG2 expression in human lung cancers. We show that E2F1 causes chemotherapeutic drug efflux both in vitro and in vivo via ABCG2. Furthermore, the E2F1-ABCG2 axis suppresses chemotherapy-induced cell death that can be restored by the inhibition of ABCG2. These findings therefore identify a new axis in multidrug resistance and highlight a radical new function of E2F1 that is relevant to tumor therapy.
