RESUMO
Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
Assuntos
Fator de Transcrição E2F1/metabolismo , Glicoproteínas de Membrana/metabolismo , Poro Nuclear/fisiologia , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Carcinogênese , Núcleo Celular/metabolismo , Proliferação de Células , Fator de Transcrição GATA2/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Membrana Nuclear , Complexo de Proteínas Formadoras de Poros Nucleares , Transdução de SinaisRESUMO
Sepsis, the systemic response to infection, is a life-threatening situation for patients and leads to high mortality, especially when caused by antimicrobial resistant pathogens. Prompt diagnosis and identification of the pathogenic bacteria, including their antibiotic resistance, are highly desired to yield a timely decision for treatment. Here, we aim to develop a platform for rapid isolation and efficient identification of Staphylococcus aureus, the most frequently occurring pathogen in sepsis. A peptide (VPHNPGLISLQG, SA5-1), specifically binding to S. aureus, was conjugated to the PEGylated magnetic nanoclusters, successfully enabling the specific capture and enrichment of S. aureus from blood serum. Consequently, fast detection of the antimicrobial resistance of the collected S. aureus was achieved within 30 min using a novel luminescent probe. These magnetic nanoclusters manifest a promising diagnostic prospect to combat sepsis.