Radiation therapy promotes unsaturated fatty acids to maintain survival of glioblastoma.

Autor: De Martino M; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA., Daviaud C; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA., Minns HE; Department of Pediatrics, Pediatrics Hematology/Oncology/Stem Cell Transplant, Columbia University Irving Medical Center, New York, NY, USA., Lazarian A; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Wacker A; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Costa AP; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Attarwala N; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA., Chen Q; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA., Choi SW; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., Rabadàn R; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA., McIntire LBJ; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Gartrell RD; Department of Pediatrics, Pediatrics Hematology/Oncology/Stem Cell Transplant, Columbia University Irving Medical Center, New York, NY, USA., Kelly JM; Department of Radiology, Weill Cornell Medicine, New York, NY, USA., Laiakis EC; Department of Oncology, Georgetown University, Washington, DC, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA., Vanpouille-Box C; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA. Electronic address: clv2002@med.cornell.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2023 Aug 28; Vol. 570, pp. 216329. Date of Electronic Publication: 2023 Jul 26.
DOI: 10.1016/j.canlet.2023.216329
Abstrakt: Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. Here, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increased formation of lipid droplets to prevent endoplasmic reticulum (ER) stress. The reduction of lipid accumulation with genetic suppression and pharmacological inhibition of the fatty acid synthase (FASN), one of the main lipogenic enzymes, leads to mitochondrial dysfunction and increased apoptosis of irradiated GBM cells. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. Overall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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