Loss of LKB1-NUAK1 signalling enhances NF-κB activity in a spheroid model of high-grade serous ovarian cancer

• Published in: Scientific reports Vol. 12; no. 1; p. 3011
• Main Authors: Buensuceso, Adrian, Fritz, Jamie Lee, Collins, Olga, Valdés, Yudith Ramos, Borrelli, Matthew J., DiMattia, Gabriel E., Shepherd, Trevor G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/80; AMP-Activated Protein Kinase Kinases - genetics; AMP-Activated Protein Kinase Kinases - physiology; Animal models; Animals; Cell Survival; Cell viability; Chemotherapy; Cytotoxicity; Disease Models, Animal; Epithelial cells; Fallopian tube; Female; Gene Expression Profiling; Humanities and Social Sciences; Humans; Inflammation; LKB1 protein; Loss of Function Mutation; Malignancy; Metastases; Metastasis; Mice; Molecular Targeted Therapy; multidisciplinary; Neoplasm Transplantation; NF-kappa B - metabolism; NF-κB protein; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Protein Kinases - genetics; Protein Kinases - physiology; Reactive oxygen species; Reactive Oxygen Species - metabolism; RelB protein; Repressor Proteins - genetics; Repressor Proteins - physiology; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Spheroids; Spheroids, Cellular - metabolism; Spheroids, Cellular - physiology; Transcription factors; Transcriptome - genetics; Transcriptomes; Tumor Cells, Cultured; Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-06796-2

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.