Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite the multimodal standard treatments for GBM, the median survival is still about one year. Analysis of brain tissues from GBM patients shows that lipid droplets are highly enriched in tumor tissues while undetectable in normal brain tissues, yet the identity and functions of lipid species in GBM are not well understood. The aims of the present work are to determine how GBM utilizes fatty acids, and assess their roles in GBM proliferation. Treatment of U138 GBM cells with a monounsaturated fatty acid, oleic acid, induces accumulation of perilipin 2-coated lipid droplets containing triglycerides enriched in C18:1 fatty acid, and increases fatty acid oxidation. Interestingly, oleic acid also increases glucose utilization and proliferation of GBM cells. In contrast, pharmacologic inhibition of monoacylglycerol lipase attenuates GBM proliferation. Our findings demonstrate that monounsaturated fatty acids promote GBM proliferation via triglyceride metabolism, suggesting a novel lipid droplet-mediated pathway which may be targeted for GBM treatment.
Highlights
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults
The analysis of lipid content by thin-layer chromatography (TLC) showed that oleic acid treatment increased fatty acid incorporation into TAGs in both GBM cells and normal astrocytic cells compared to the control condition (Fig. 1B)
In the brain, using electron microscopy and fluorescence imaging, it has been observed that tumor tissues from GBM patients contain large amounts of LDs24
Summary
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor in adults. Treatment of U138 GBM cells with a monounsaturated fatty acid, oleic acid, induces accumulation of perilipin 2-coated lipid droplets containing triglycerides enriched in C18:1 fatty acid, and increases fatty acid oxidation. Our findings demonstrate that monounsaturated fatty acids promote GBM proliferation via triglyceride metabolism, suggesting a novel lipid droplet-mediated pathway which may be targeted for GBM treatment. Oral administration of stable isotope labeled [13C] fatty acids to mice by gastric gavage showed a strong [13C] enrichment in gliomas and only low level of [13C] enrichment in the capillary endothelial cells of normal brain[10]. These results were supported by previous study showing that the blood-brain barrier in experimental brain metastases was impaired[11]. In the central nervous system, LD levels are barely detectable, recent studies show that neurons and glia accumulate LDs under disease conditions such as brain tumors[19,20]
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