Lipid accumulation and oxidation in glioblastoma multiforme

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.

Assessing fatty acid-induced lipotoxicity and its therapeutic potential in glioblastoma using stimulated Raman microscopy

“…But inhibition of LDs rescued PA-induced lipotoxicity, the reason for which is unclear. It has been reported that PA or EPA treatment-induced apoptosis while OA treatment increased the proliferation rate of glioma cells 23 , 36 , 37 , which are consistent with our results. And the inhibition of DGAT1 in PA-treated cells would increase C16 ceramide which induced tumor growth while C18 ceramide did not 11 , 55 , inferring that inhibition of PA-induced LDs may lead to a worse outcome in treating gliomas.…”

“…We observed and quantified LDs formation and changes of unsaturation level of LD lipids with label-free SRS imaging. We found that PA or EPA treatment reduced glioma cell viability, but OA treatment enhanced cell viability and proliferation, which were consistent with the previous studies 23 , 36 , 37 . By inhibiting the final step of the biosynthesis of TAG (i.e., inhibiting DGAT1 and DGAT2) for LDs formation 38 – 41 , the LDs were significantly reduced with all three FAs treatments.…”

“…7 B). These results indicate that uptake of OA was beneficial for glioma proliferation and it may be inadvisable to introduce lipotoxicity by treating extra OA on purpose 23 , 53 . Most interestingly, 200 µM EPA-treated cells underwent a clear drop in cell survival rate (69.6% ± 3.5%) showing its highest lipotoxicity to U87 glioma cells.…”

“…Based on the degree of unsaturation (i.e., the number of double bonds), FAs could be classified into saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs). In GBM tissue, the most abundant two FAs are palmitic acid (PA; 16:0) and oleic acid (OA; 18:1) 23 . It is also reported that ω3-PUFAs, such as eicosapentaenoic acid (EPA; 20:5), induced cell death and increased radiotherapy responsiveness of glioma cells 24 , 25 .…”

Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

“…Lipid metabolism is abnormally regulated in gliomas compared to normal cells, with changes in the expression of lipid-related genes such as SREBP1 and FAS, which results in altered lipid composition and lipogenesis to keep up with energy demands. 10,14,15 Lipid droplets are cytosolic organelles that, among other functions, serve as a storage medium for the fatty acids used as an energy source to maintain rapid proliferation in unfavorable microenvironments. Lipid droplet formation particularly occurs under stressful conditions such as hypoxia and nutrient deprivation.…”