Alkylphospholipids deregulate cholesterol metabolism and induce cell-cycle arrest and autophagy in U-87 MG glioblastoma cells.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2013-08-01; 1831(8): 1322-1334
DOI: 10.1016/j.bbalip.2013.05.004
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Ríos-Marco P(1), Martín-Fernández M, Soria-Bretones I, Ríos A, Carrasco MP, Marco C.
Author information:
(1)Department of Biochemistry and Molecular Biology I, University of Granada,
Granada, Spain.
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.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbalip.2013.05.004
PMID: 23707264 [Indexed for MEDLINE]