Your browser doesn't support javascript.
loading
Loss of LKB1-NUAK1 signalling enhances NF-κB activity in a spheroid model of high-grade serous ovarian cancer.
Buensuceso, Adrian; Fritz, Jamie Lee; Collins, Olga; Valdés, Yudith Ramos; Borrelli, Matthew J; DiMattia, Gabriel E; Shepherd, Trevor G.
Afiliación
  • Buensuceso A; The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
  • Fritz JL; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Collins O; The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
  • Valdés YR; Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
  • Borrelli MJ; The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
  • DiMattia GE; The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
  • Shepherd TG; The Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
Sci Rep ; 12(1): 3011, 2022 02 22.
Article en En | MEDLINE | ID: mdl-35194062
High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy often diagnosed at an advanced stage. Although most HGSOC patients respond initially to debulking surgery combined with cytotoxic chemotherapy, many ultimately relapse with platinum-resistant disease. Thus, improving outcomes requires new ways of limiting metastasis and eradicating residual disease. We identified previously that Liver kinase B1 (LKB1) and its substrate NUAK1 are implicated in EOC spheroid cell viability and are required for efficient metastasis in orthotopic mouse models. Here, we sought to identify additional signalling pathways altered in EOC cells due to LKB1 or NUAK1 loss-of-function. Transcriptome analysis revealed that inflammatory signalling mediated by NF-κB transcription factors is hyperactive due to LKB1-NUAK1 loss in HGSOC cells and spheroids. Upregulated NF-κB signalling due to NUAK1 loss suppresses reactive oxygen species (ROS) production and sustains cell survival in spheroids. NF-κB signalling is also activated in HGSOC precursor fallopian tube secretory epithelial cell spheroids, and is further enhanced by NUAK1 loss. Finally, immunohistochemical analysis of OVCAR8 xenograft tumors lacking NUAK1 displayed increased RelB expression and nuclear staining. Our results support the idea that NUAK1 and NF-κB signalling pathways together regulate ROS and inflammatory signalling, supporting cell survival during each step of HGSOC pathogenesis. We propose that their combined inhibition may be efficacious as a novel therapeutic strategy for advanced HGSOC.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Proteínas Quinasas / Proteínas Represoras / Transducción de Señal / FN-kappa B / Esferoides Celulares / Mutación con Pérdida de Función / Quinasas de la Proteína-Quinasa Activada por el AMP Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Rep Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Proteínas Quinasas / Proteínas Represoras / Transducción de Señal / FN-kappa B / Esferoides Celulares / Mutación con Pérdida de Función / Quinasas de la Proteína-Quinasa Activada por el AMP Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Rep Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido