title: Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids.
abstract: Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5'-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor.
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peart
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Yudith
authors.initials: Y
authors.lastname: Ramos Valdes
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Rohann J M
authors.initials: RJ
authors.lastname: Correa
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Fazio
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Monique
authors.initials: M
authors.lastname: Bertrand
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: McGee
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Préfontaine
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Akira
authors.initials: A
authors.lastname: Sugimoto
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: DiMattia
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada.|Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.|Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Shepherd
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014162:Transfection
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; LKB1; ovarian cancer; spheroid; tumour cell dormancy