Glioma cells survival depends both on fatty acid oxidation and on functional carnitine transport by SLC22A5

Abstract

Gliomas are the most common primary malignant brain tumor in adults, but current treatment for glioblastoma multiforme (GBM) is insufficient. Even though glucose is the primary energetic substrate of glioma cells, they are capable of using fatty acids to generate energy. Fatty acid oxidation (FAO) in mitochondria requires L‐carnitine for the formation of acylcarnitines by carnitine palmitoylotransferase 1 (CPT1) and further transport of acyl carnitine esters to mitochondrial matrix. Carnitine can be delivered to the cell by an organic cation/carnitine transporter—SLC22A5/OCTN2. In this study, we show that SLC22A5 is up‐regulated in glioma cells and that they vary in the amount of SLC22A5 in the plasma membrane. Research on glioma cells (lines U87MG, LN229, T98G) with various expression levels of SLC22A5 demonstrated a correlation between the FAO rate, the level of the transporter, and the carnitine transport. Inhibition of carnitine transport by chemotherapeutics, such as vinorelbine and vincristine, led to inhibition of FAO, which was further intensified by etomoxir—a CPT1 inhibitor. This led to reduced viability and increased apoptosis in glioma cells. Modulation of SLC22A5 level by either silencing or up‐regulation of SLC22A5 also affected glioma cell survival in a FAO‐dependent way. These observations suggest that the survival of glioma cells is heavily reliant on both FAO and SLC22A5 activity, as well as that CPT1 and SLC22A5 might be possible drug targets.

Effective Detection and Monitoring of Glioma Using [18F]FPIA PET Imaging

“…Interestingly, SLC22A5 has also been implicated in pivaloyl-carnitine transport [30]; therefore, it is probable that the pivaloyl-carnitine metabolite of [ 18 F]FPIA is transported from the systemic circulation into tumor cells via SLC22A5. Interestingly, SLC22A5 has been recently reported to be critical for the survival of glioma cells [31,32], supporting increased fatty acid metabolism, which is possibly mirrored in our positive correlation with [ 18 F]FPIA uptake.…”

Beyond glucose: alternative sources of energy in glioblastoma

“…Utilizing a Seahorse Analyzer to measure oxygen consumption rate (a measure of the oxygen-dependent metabolic activity occurring in a cell), a comparison of the oxygen consumption of hGBM treated with linoleic acid and etomoxir (to inhibit fatty acid oxidation) and that of hGBM treated with FCCP and antimycin A (to induce maximal oxidative respiration) was conducted, and the comparison revealed that a significant majority, nearly 80%, of oxygen respiration is dependent of fatty acid oxidation 15 . This dependence of glioma on fatty acid oxidation was corroborated by Juraszek et al and Fink et al, who both measured the expression of SLC22A5/OCTN2 (an organic transporter that delivers carnitine to a cell and is an important component of fatty acid oxidation) and found it to be overexpressed in human glioma cells 16 , 17 . In addition, they observed a decrease in viability and an increase in apoptosis in human glioma cells in response to inhibition of fatty acid oxidation 16 , a finding that was also reported by Bi and colleagues 18 .…”

“…This dependence of glioma on fatty acid oxidation was corroborated by Juraszek et al and Fink et al, who both measured the expression of SLC22A5/OCTN2 (an organic transporter that delivers carnitine to a cell and is an important component of fatty acid oxidation) and found it to be overexpressed in human glioma cells 16 , 17 . In addition, they observed a decrease in viability and an increase in apoptosis in human glioma cells in response to inhibition of fatty acid oxidation 16 , a finding that was also reported by Bi and colleagues 18 . Thus, fatty acid oxidation contributes heavily to the generation of energy of gliomas and, as such, presents an avenue of research critical to our understanding of how gliomas subvert normal energy production in order to maintain aberrant growth and proliferation 14 .…”

“…Further, the activity of fatty acid oxidation in GBM has been experimentally shown to contribute to aerobic respiration. Enzymes involved in fatty acid oxidation, particularly carnitine palmitoyltransferase and long-chain acyl-CoA dehydrogenase, have been found to be upregulated in human glioma tissue 15 , 16 . Lin et al also determined the degree to which aerobic respiration in the mitochondria is dependent on fatty acids.…”

Orbitrap‐MS‐based untargeted metabolomics study on the therapeutic effect of colchicine on myocardial infarction

“…Fatty acids are important energy storage substances in the human body, and the β ‐oxidation of fatty acids is an important energy source for cell growth and survival (Juraszek et al, 2020). At present, there are few studies on the mechanism of action and medicinal mechanism of omega‐6 unsaturated fatty acids in cardiovascular field (Alhusseiny & El‐Beshbishi, 2020).…”