Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids
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Teresa Peart1,2, Yudith Ramos Valdes1, Rohann J. M. Correa1,3, Elena Fazio1,2, Monique Bertrand1,4,5, Jacob McGee1,4, Michel Préfontaine1,4, Akira Sugimoto1,4,5, Gabriel E. DiMattia1,3,4,5, Trevor G. Shepherd1,2,4,5
1Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, Canada
2Departments of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
3Departments of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
4Departments of Obstetrics & Gynaecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
5Departments of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada
Trevor G. Shepherd, e-mail: [email protected]
Keywords: ovarian cancer, spheroid, LKB1, AMPK, tumour cell dormancy
Received: May 14, 2015 Accepted: May 23, 2015 Published: June 05, 2015
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.
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