Alkylphospholipids deregulate cholesterol metabolism and induce cell-cycle arrest and autophagy in U-87 MG glioblastoma cells
| Autor: | Antonio Ríos, Carmen Marco, Mario Martín-Fernández, María P. Carrasco, Isabel Soria-Bretones, Pablo Ríos-Marco |
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| Přispěvatelé: | Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España) |
| Rok vydání: | 2013 |
| Předmět: |
Biological Transport
Active Antineoplastic Agents Biology Cell-cycle arrest U-87 MG cell Lysosome Cell Line Tumor Lysosomal-Associated Membrane Protein 2 medicine Autophagy Humans Cholesterol homeostasis neoplasms Molecular Biology Late endosome Phospholipids LAMP2 Cell growth Brain Neoplasms Endoplasmic reticulum Alkylphospholipid Lysosome-Associated Membrane Glycoproteins Lipid metabolism Cell Biology Cell biology Neoplasm Proteins G2 Phase Cell Cycle Checkpoints medicine.anatomical_structure Cholesterol Receptors LDL LDL receptor M Phase Cell Cycle Checkpoints Hydroxymethylglutaryl CoA Reductases lipids (amino acids peptides and proteins) Glioblastoma |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Glioblastoma is the most common malignant primary brain tumour in adults and one of the most lethal of all cancers. Growing evidence suggests that human tumours undergo abnormal lipid metabolism, characterised by an alteration in the mechanisms that regulate cholesterol homeostasis. We have investigated the effect that different antitumoural alkylphospholipids (APLs) exert upon cholesterol metabolism in the U-87 MG glioblastoma cell line. APLs altered cholesterol homeostasis by interfering with its transport from the plasma membrane to the endoplasmic reticulum(ER), thus hindering its esterification. At the same time they stimulated the synthesis of cholesterol from radiolabelled acetate and its internalisation from low-density lipoproteins (LDLs), inducing both 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and LDL receptor (LDLR) genes. Fluorescent microscopy revealed that these effects promoted the accumulation of intracellular cholesterol. Filipin staining demonstrated that this accumulation was not confined to the late endosome/lysosome (LE/LY) compartment since it did not colocalise with LAMP2 lysosomal marker. Furthermore, APLs inhibited cell growth, producing arrest at the G2/M phase. We also used transmission electron microscopy (TEM) to investigate ultrastructural alterations induced by APLs and found an abundant presence of autophagic vesicles and autolysosomes in treated cells, indicating the induction of autophagy. Thus our findings clearly demonstrate that antitumoural APLs interfere with the proliferation of the glioblastoma cell line via a complex mechanism involving cholesterol metabolism, cell-cycle arrest or autophagy. Knowledge of the interrelationship between these processes is fundamental to our understanding of tumoural response and may facilitate the development of novel therapeutics to improve treatment of glioblastoma and other types of cancer. © 2013 Elsevier B.V. This research was aided by the Andalusian regional government (CTS-236). The authors thank Xiomara Gálvez for her technical support and Dr. Francisco D. Martín for his help in our fluorescence microscopy experiments. Pablo Ríos-Marco holds a fellowship from the Spanish Ministry of Education |
| Databáze: | OpenAIRE |
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