Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells

Abstract

Background.Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.Methods.We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.Results.We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.Conclusions.Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

“…S8A). Second, to assess the contribution of FAO in OxPhos, we measured ORR after cell treatment with DMSO vehicle or FAO inhibitor Etomoxir (48,49). We found that the ΔORR between DMSO-and Etomoxir-treated cells was lower in shCDCP1-transduced than in shScramble-transduced cells (Fig.…”

Neurotoxicity of pre-incubated alpha-synuclein with neutral nanoliposomes on PC12 and SHSY5Y cell lines

“…With this interpretation, it has been recently identi ed that oxidation of fatty acids is essential for malignant glioma cells (Glioma is of primary malignant brain tumor in adult) in which targeting this metabolic pathway leads to decreasing energy, and consequently reducing cell proliferation. In other words, besides glucose, the cancer cells use lipid for their respiratory activity [48].…”

shRNA‐mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth

“…PPARα drives the transcription of key fatty acid oxidation (FAO) enzymes, including carnitine palmitoyltransferase 1 alpha (CPT1α; CPT1A ) and acyl‐coenzyme A oxidase 1 (ACOX1) . Both murine sub‐ventricular zone NSC and human GSC have been reported as being dependent on FAO . In this study, PPARα KD reduced the gene expression of CPT1A and ACOX1, with a concomitant reduction in proliferation and clonogenic potential.…”

“…This may be due to the reduction in c‐Myc expression, which has been associated with decreased glycolytic rates . In addition, we propose that FAO‐dependent GSC have only a small requirement for glucose oxidation , and PPARα KD, through effects on FAO enzyme expression, may deplete GSC populations of their prime FAO bioenergetic source with no compensatory glycolytic flux, resulting in the anti‐proliferative phenotype described. Interestingly, the unique metabolic requirements of GSC compared to the aberrantly differentiated cells of the tumour mass may explain the paradox of increased PPARA expression in mediating prolonged clinical survival versus KD of PPARα in GSC inhibiting tumour growth.…”