Department 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.
Human Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, 63122 Clermont-Ferrand, France.
Cell Rep. 2023 Jul 25;42(7):112790. doi: 10.1016/j.celrep.2023.112790. Epub 2023 Jul 11.
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.
胆固醇是细胞膜的结构组成部分。快速生长的肿瘤细胞如何维持膜胆固醇的动态平衡，目前还知之甚少。在这里，我们发现胶质母细胞瘤（GBM），即最致命的脑肿瘤，维持着正常水平的膜胆固醇，但在其脂滴（LD）中有大量的胆固醇酯（CE）。从机制上讲，SREBP-1（固醇调节元件结合蛋白 1）是一种在胆固醇耗竭时被激活的主转录因子，它上调关键的自噬基因，包括 ATG9B、ATG4A 和 LC3B，以及溶酶体胆固醇转运蛋白 NPC2。这种上调促进 LD 脂解，导致 CE 水解，并从溶酶体中释放胆固醇，从而维持质膜胆固醇的动态平衡。当这条通路被阻断时，GBM 细胞在体外对胆固醇缺乏非常敏感，生长不良。我们的研究揭示了 SREBP-1-自噬-LD-CE 水解途径在维持膜胆固醇动态平衡方面的重要作用，同时为 GBM 提供了一种潜在的治疗途径。
