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Determining the role of lipid droplets and their therapeutic potential in glioblastoma

确定脂滴在胶质母细胞瘤中的作用及其治疗潜力

基本信息

批准号：
10735417
负责人：
Deliang Guo
金额：
$ 55.86万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735417
关键词：
Adult Antioxidants Autophagocytosis Biology Brain Neoplasms Cell Death Cell Proliferation Cell membrane Cells Cellular Membrane Cellular Structures Cholesterol Cholesterol Esters Cholesterol Homeostasis Clinic Cystine Data Defense Mechanisms Diagnosis Drops Drug Metabolic Detoxication Enzymes Fatty Acids Funding Genes Glioblastoma Glucose Goals Growth Homeostasis Hydrolysis In Vitro Induction of Apoptosis Laboratories Lipids Malignant Neoplasms Measures Mediating Membrane Membrane Structure and Function Metabolism Mitochondria Names Oleic Acids Outcome Pathway interactions Play Pre-Clinical Model Primary Brain Neoplasms Prognosis Public Health Reactive Oxygen Species Regulation Resistance Resources Role Starvation Stearic Acids Stearoyl-CoA Desaturase Testing Therapeutic Tissues Toxic effect Translating Triglycerides Up-Regulation Xenograft Model cell growth cell injury cholesterol control combinatorial diacylglycerol O-acyltransferase effective therapy endoplasmic reticulum stress experimental study fatty acid oxidation in vivo inhibition of autophagy insight lipidomics neoplastic cell novel novel strategies oxidation pharmacologic pre-clinical prevent response synergism therapeutically effective tumor tumor growth uptake

项目摘要

ABSTRACT Over the past two decades, the prognosis for glioblastoma (GBM), the most lethal brain tumor, has remained dismal, with a median survival of only 12-16 months from diagnosis. We recently demonstrated that GBM cells acquire large amounts of fatty acids (FAs) and cholesterol by dramatically upregulating their de novo synthesis and uptake for rapid tumor growth. However, excess FAs and cholesterol can alter membrane dynamics and function, leading to cellular damage. How GBM cells avoid this lipotoxicity to sustain proper lipid levels in different cellular compartments, particularly in the mitochondria, is poorly understood. During the past 5 years of funding, we have made great progress in understanding how GBM controls FA homeostasis. We demonstrated that GBM cells upregulate diacylglycerol acyltransferase 1 (DGAT1), allowing them to store abundant FAs as triacylglycerol-containing lipid droplets (LDs) to prevent excess FA accumulation to induce toxicity. In this renewal proposal, we will address two unanswered critical questions: 1) how is cholesterol homeostasis regulated in GBM cells? and 2) can effective therapeutic approaches be developed for GBM by disrupting lipid homeostasis? We recently found that cholesteryl esters (CEs), which form LDs to store excess cellular cholesterol, are largely present in GBM tissues, and blocking CE synthesis results in dramatic mitochondrial fragmentation in GBM cells. Moreover, our preliminary data showed that cholesterol is transferred from CE- containing LDs (CE-LDs) to the plasma membrane, while inhibition of autophagy blocks this transfer. These data suggest that CE-LDs maintain proper cellular cholesterol levels via autophagy. Our preliminary data further showed that stearoyl-CoA desaturase 1 (SCD1), which has been shown to prevent endoplasmic reticulum (ER) stress and ferroptosis, is upregulated upon DGAT1 inhibition. Finally, preliminary data showed that the expression of multiple antioxidant genes is significantly elevated in response to DGAT1 inhibition. These results strongly suggest that GBM cells can activate defense mechanisms to alleviate the lipotoxicity triggered by disruption of FA storage, possibly leading to tumor resistance to DGAT1 inhibition. Thus, we hypothesize that CE-LDs serve as critical reservoirs for controlling cholesterol homeostasis and mitochondrial function, and that combining disruption of storage or redistribution of cholesterol with interference with mitochondrial cholesterol import, or disruption of FA storage with either inhibition of SCD1 or blockade of antioxidant pathways are effective strategies for targeting GBM. In Aim 1, we will examine the impact of inhibiting cholesterol storage or redistribution from CE-LDs on cholesterol homeostasis and mitochondrial function, and whether such blockade can synergize with interfering in cholesterol import into mitochondria to efficiently kill tumor cells in GBM xenograft models. In Aim 2, we will examine whether inhibiting SCD1 or antioxidant pathways can strongly synergize with DGAT1 inhibition to effectively inhibit GBM growth in vitro and in vivo. Successful completion of this study will provide strong pre-clinical data on potential novel strategies to target GBM.

摘要