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

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. The effectiveness of traditional therapies for GBM is limited and therefore new therapies are highly desired. Previous studies show that lipid metabolism reprogramming may be a potential therapeutic target in GBM. This study aims to evaluate the therapeutic potential of free fatty acid-induced lipotoxicity for the suppression of glioma growth. U87 glioma cells are treated with three fatty acids (FAs): palmitic acid (PA), oleic acid (OA), and eicosapentaenoic acid (EPA). Uptake of the FAs and formation of lipid droplets (LDs) are imaged and quantified using a lab-built stimulated Raman scattering (SRS) microscope. Our results show that a supply of 200 µM PA, OA, and EPA leads to efficient LDs accumulation in glioma cells. We find that inhibition of triglycerides (TAGs) synthesis depletes LDs and enhances lipotoxicity, which is evidenced by the reduced cell proliferation rates. In particular, our results suggest that EPA treatment combined with depletion of LDs significantly reduces the survival rate of glioma cells by more than 50%, indicating the therapeutic potential of this approach. Future work will focus on understanding the metabolic mechanism of EPA-induced lipotoxicity to further enhance its anticancer effects.

Integrative Metabolomics Reveals Deep Tissue and Systemic Metabolic Remodeling in Glioblastoma

“…Lipid droplets (LDs) are organelles that are commonly found in fatty tissues storing lipids, triglycerol, and cholesterol esters. Recently, the presence of LDs has been demonstrated in glial and glioblastoma cell cultures in vivo [73]. These LDs are not only a simple reservoir of fatty acids but have an impact on important cell processes such as cell cycles, cell migration of glial cells, and their resistance to apoptosis and conventional treatments [69].…”

“…It has been established for a long time [75] that GBM diverts brain lipid metabolism to its advantage to sustain the energy stores needed for their own expansion. By focusing on these LDs, it has been shown that they play a central role in this lipid metabolism reprogramming [73]. Furthermore, it has been reported that autophagy-mediated hydrolysis of these LD maintains energy homeostasis [76].…”

Targeting the Sphingolipid Rheostat in Gliomas

“…Upon entering the glioma cell, PA can be dedicated to various pathways, including beta-oxidation, membrane lipid production, or sphingolipid biosynthesis. However, excess PA accumulation induces lipotoxicity in T98G [ 42 ] and U87 GBM cells [ 43 ] by triggering the formation of ROS and promoting the ER stress pathways [ 42 ]. This can ultimately lead to apoptosis at PA concentrations greater than 300 μM [ 42 , 43 ].…”

Lipid profiling using Raman and a modified support vector machine algorithm

“…[5] In biomedical research, Raman spectroscopy has emerged as a novel technique in measuring the chemical composition and molecular structure of cells and tissues. [6][7][8][9][10] Molecular changes are reflected in the spectra of diseased tissues, compared to those of the healthy ones, and are recognized as biochemical markers of the ex vivo and in vivo diseases. [8,[11][12][13][14] Fatty acids of lipid droplets (LDs) are recognized as biochemical markers in cancer cells and liver fibrosis.…”