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: Teresa Peart, Yudith Ramos Valdes, Rohann J M Correa, Elena Fazio, Monique Bertrand, Jacob McGee, Michel Préfontaine, Akira Sugimoto, Gabriel E DiMattia, Trevor G Shepherd
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 26 Pg. 22424-38 (Sep 08 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26068970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (metabolism)
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Cell Survival (physiology)
• Female
• Humans
• Neoplasms, Glandular and Epithelial (enzymology, genetics, pathology)
• Ovarian Neoplasms (enzymology, genetics, pathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• Spheroids, Cellular
• Transfection