RESUMEN
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-jun/genética , ARN Polimerasa II/metabolismo , Receptores de Somatomedina/metabolismo , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Núcleo Celular/patología , Supervivencia Celular/genética , Cromatina/genética , Cromatina/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Regiones Promotoras Genéticas/genética , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptor IGF Tipo 1 , Transducción de Señal/genética , Sitio de Iniciación de la Transcripción , Regulación hacia ArribaRESUMEN
Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.
Asunto(s)
Descubrimiento de Drogas , Indazoles/síntesis química , Microsomas Hepáticos/efectos de los fármacos , Triazoles/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/química , Indazoles/uso terapéutico , Estructura Molecular , Distrofia Muscular de Duchenne/tratamiento farmacológico , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.
