Abstract
Cellular metabolic changes, especially to lipid metabolism, have recently been recognized as a hallmark of various cancer cells. However, little is known about the significance of cellular lipid metabolism in the regulation of biological activity of glioma stem cells (GSCs). In this study, we examined the expression and role of fatty acid synthase (FASN), a key lipogenic enzyme, in GSCs. In the de novo lipid synthesis assay, GSCs exhibited higher lipogenesis than differentiated non-GSCs. Western blot and immunocytochemical analyses revealed that FASN is strongly expressed in multiple lines of patient-derived GSCs (G144 and Y10), but its expression was markedly reduced upon differentiation. When GSCs were treated with 20 μM cerulenin, a pharmacological inhibitor of FASN, their proliferation and migration were significantly suppressed and de novo lipogenesis decreased. Furthermore, following cerulenin treatment, expression of the GSC markers nestin, Sox2 and fatty acid binding protein (FABP7), markers of GCSs, decreased while that of glial fibrillary acidic protein (GFAP) expression increased. Taken together, our results indicate that FASN plays a pivotal role in the maintenance of GSC stemness, and FASN-mediated de novo lipid biosynthesis is closely associated with tumor growth and invasion in glioblastoma.
Highlights
Of the gliomas, glioblastoma has the poorest prognosis, with a median survival rate between 1 and 2 years [1]
We first explored whether incorporation of glucose or acetate into the lipid fraction representing de novo lipogenesis [26] is altered between glioma stem cells (GSCs) and differentiated non-GSCs. 14[C]-Glucose incorporation was significantly higher in GSCs than in differentiated non-GSCs (65.38 ± 4.45 DPM/μg in G144; 48.16 ± 3.76 DPM/μg in Y10; 86.52 ± 11.30 DPM/μg in G179 vs. 32.32 ± 0.82 DPM/μg in dif-G144; 12.38 ± 0.48 DPM/μg in dif-Y10; 34.09 ± 1.38 DPM/μg in dif-G179; P < 0.01; Fig 1A)
fatty acid synthase (FASN) was highly detected in the cytoplasm of human glioblastoma cells, and FASN was frequently co-localized with Sox2, a marker of GSC (Fig 2A)
Summary
Glioblastoma has the poorest prognosis, with a median survival rate between 1 and 2 years [1]. Glioblastoma is resistant to radiation and chemotherapy, and glioma stem cells (GSCs) are thought to be partially responsible for the resistance to therapy, recurrence, and invasiveness [2, 3]. Elucidating the molecular mechanisms that regulated the biological activity of GSCs is important for identifying novel therapeutic targets. Metabolic reprogramming is thought to be a new hallmark of cancer [4]. Cancer cells including glioblastoma has been reported to rely on glycolysis than on oxidative phosphorylation for PLOS ONE | DOI:10.1371/journal.pone.0147717. Cancer cells including glioblastoma has been reported to rely on glycolysis than on oxidative phosphorylation for PLOS ONE | DOI:10.1371/journal.pone.0147717 January 25, 2016
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