Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism
Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724004300 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841542497200766976 |
|---|---|
| author | Bayan Alkotub Lisa Bauer Ali Bashiri Dezfouli Khouloud Hachani Vasilis Ntziachristos Gabriele Multhoff Morteza Hasanzadeh Kafshgari |
| author_facet | Bayan Alkotub Lisa Bauer Ali Bashiri Dezfouli Khouloud Hachani Vasilis Ntziachristos Gabriele Multhoff Morteza Hasanzadeh Kafshgari |
| author_sort | Bayan Alkotub |
| collection | DOAJ |
| description | Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells.In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles. |
| format | Article |
| id | doaj-art-c47429d786da4b068cbe1d2182f80f3b |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-c47429d786da4b068cbe1d2182f80f3b2025-01-14T04:12:07ZengElsevierRedox Biology2213-23172025-02-0179103452Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolismBayan Alkotub0Lisa Bauer1Ali Bashiri Dezfouli2Khouloud Hachani3Vasilis Ntziachristos4Gabriele Multhoff5Morteza Hasanzadeh Kafshgari6Institute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München, Neuherberg, Germany; Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, GermanyRadiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Department of Radiation Oncology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, GermanyRadiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Department of Otorhinolaryngology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, GermanyRadiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Department of Otorhinolaryngology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, GermanyInstitute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München, Neuherberg, Germany; Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, GermanyRadiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Department of Radiation Oncology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Corresponding author. Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Department of Radiation Oncology, TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany; Corresponding author. Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany.Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells.In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles.http://www.sciencedirect.com/science/article/pii/S2213231724004300FenofibrateGlioblastomaRadiotherapyLipid dropletsDGAT1GPAT4 |
| spellingShingle | Bayan Alkotub Lisa Bauer Ali Bashiri Dezfouli Khouloud Hachani Vasilis Ntziachristos Gabriele Multhoff Morteza Hasanzadeh Kafshgari Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism Redox Biology Fenofibrate Glioblastoma Radiotherapy Lipid droplets DGAT1 GPAT4 |
| title | Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| title_full | Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| title_fullStr | Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| title_full_unstemmed | Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| title_short | Radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| title_sort | radiosensitizing capacity of fenofibrate in glioblastoma cells depends on lipid metabolism |
| topic | Fenofibrate Glioblastoma Radiotherapy Lipid droplets DGAT1 GPAT4 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724004300 |
| work_keys_str_mv | AT bayanalkotub radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT lisabauer radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT alibashiridezfouli radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT khouloudhachani radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT vasilisntziachristos radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT gabrielemulthoff radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism AT mortezahasanzadehkafshgari radiosensitizingcapacityoffenofibrateinglioblastomacellsdependsonlipidmetabolism |