SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells
Summary: Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472300801X |
| _version_ | 1797782678367371264 |
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| author | Feng Geng Yaogang Zhong Huali Su Etienne Lefai Shino Magaki Timothy F. Cloughesy William H. Yong Arnab Chakravarti Deliang Guo |
| author_facet | Feng Geng Yaogang Zhong Huali Su Etienne Lefai Shino Magaki Timothy F. Cloughesy William H. Yong Arnab Chakravarti Deliang Guo |
| author_sort | Feng Geng |
| collection | DOAJ |
| description | Summary: Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM. |
| first_indexed | 2024-03-13T00:14:19Z |
| format | Article |
| id | doaj.art-3f47a5ba3dcf439c8df372f6c94a73fc |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T00:14:19Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3f47a5ba3dcf439c8df372f6c94a73fc2023-07-12T04:19:25ZengElsevierCell Reports2211-12472023-07-01427112790SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cellsFeng Geng0Yaogang Zhong1Huali Su2Etienne Lefai3Shino Magaki4Timothy F. Cloughesy5William H. Yong6Arnab Chakravarti7Deliang Guo8Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USADepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USADepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USAHuman Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, 63122 Clermont-Ferrand, FranceDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USADepartment of Neurology (Neuro-Oncology), David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USADepartment of Pathology and Laboratory Medicine, School of Medicine at University of California, Irvine, CA 92617, USADepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USADepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA; Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center of Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Corresponding authorSummary: Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.http://www.sciencedirect.com/science/article/pii/S221112472300801XCP: MetabolismCP: Cancer |
| spellingShingle | Feng Geng Yaogang Zhong Huali Su Etienne Lefai Shino Magaki Timothy F. Cloughesy William H. Yong Arnab Chakravarti Deliang Guo SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells Cell Reports CP: Metabolism CP: Cancer |
| title | SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| title_full | SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| title_fullStr | SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| title_full_unstemmed | SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| title_short | SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| title_sort | srebp 1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells |
| topic | CP: Metabolism CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S221112472300801X |
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