Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth

• Published in: European journal of cancer (1990) Vol. 50; no. 18; pp. 3187 - 3197
• Main Authors: Ríos, M, Foretz, M, Viollet, B, Prieto, A, Fraga, M, García-Caballero, T, Costoya, J.A, Señarís, R
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-12-2014; Elsevier
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Astrocytes - enzymology; Astrocytes - pathology; Biological and medical sciences; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Cell Proliferation - physiology; Fatty Acids - biosynthesis; Glioblastoma - enzymology; Glioblastoma - pathology; Glioma; Hematology, Oncology and Palliative Medicine; Humans; Lipid metabolism; Lipid Metabolism - physiology; Lipoprotein receptors; Medical sciences; Mice, Knockout; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; PTEN Phosphohydrolase - antagonists & inhibitors; Receptors, Lipoprotein - antagonists & inhibitors; Receptors, Lipoprotein - metabolism; Transfection; Tumor Cells, Cultured; Tumors; AMPK; Lipid metabolism; Glioma; Lipoprotein receptors; Cell proliferation; Nervous system diseases; Glioblastoma; Lipids; Activation; Malignant tumor; Lipoprotein; Metabolism; cAMP-dependent protein kinase; Carcinogenesis; Malignant glioma; Cancerology; Central nervous system disease; Cancer; Biological receptor
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.09.014

Abstract Aim of the study Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer. Methods To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients. Results We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting ‘ de novo ’ fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells. Conclusions Our findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK.