Abstract
Lipid metabolism reprogramming is a novel feature of malignancies. Identifying the vulnerability of lipid alteration in tumor cells provides a new window to treat cancer. Here, we unraveled that glioblastoma (GBM) patients containing high levels of lipid droplets (LDs), special organelles storing cholesterol esters and triglycerides in cells, presented poor survival. We found that LDs largely formed in tumor tissues from GBM patients, but rarely in low grade of gliomas and normal brain tissues, demonstrating that LDs might serve as a novel diagnostic biomarker and prognostic marker for GBM. We further revealed that sterol O-acyltransferase 1 (SOAT1), the key enzyme controlling cholesterol esterification and LD formation, is highly expressed and correlated with LD prevalence in tumor tissues from GBM patients. Genetic or pharmacologic inhibition SOAT1 using avasimibe, a phase III clinical trial drug in human atherosclerosis patients, significantly suppressed GBM growth and prolongs survival in xenograft models. Moreover, we found that inhibiting SOAT1 suppressed sterol regulatory element-binding protein-1 (SREBP-1), a key transcription factor playing a central role in lipid synthesis, underlying the molecular mechanism of targeting SOAT1-mediated GBM growth suppression. In summary, our data demonstrate that LDs/cholesterol esters uniquely formed in tumor tissues provides an ideal target to specifically inhibit GBM cells whereas sparing normal brain tissues, and reveal that blocking cholesterol storage via targeting SOAT1 represents a promising strategy for GBM treatment.
Citation Format: Feng Geng, Jeffrey Guo, Xiang Cheng, Xiaoning Wu, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets, a novel metabolic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3555. doi:10.1158/1538-7445.AM2017-3555