RESUMEN
Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade.
Asunto(s)
Metabolismo de los Lípidos , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Estearoil-CoA Desaturasa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Animales , Humanos , Masculino , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Hígado Graso/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Gastric carcinoma is a highly malignant tumor that still lacks effective molecular targets. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an essential oncogenic driver overexpressed in various cancers. The potential role of hnRNPA2B1 in oncotherapy has not been revealed because of the absence of active chemical molecules. In this study, we identified the pseudourea derivative XI-011 as a novel hnRNPA2B1 ligand using chemical proteomics. An interaction study indicated that XI-011 could bind the nucleotide-binding domain to disrupt the recruitment of hnRNPA2B1 to the promoter and untranslated region of the murine double minute X (MDMX) gene, thereby inhibiting its transcription. In addition, chemical targeting of hnRNPA2B1 recovered inactivated p53 and enhanced the therapeutic efficacy of apatinib in vivo. This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1.