Delineating how retinoic acids regulate lipid metabolism in glioblastoma and their resistance mechanisms

描述视黄酸如何调节胶质母细胞瘤中的脂质代谢及其耐药机制

基本信息

批准号：
10652468
负责人：
Deliang Guo
金额：
$ 43.2万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652468
关键词：
Acute Promyelocytic Leukemia Adult Binding Biology Brain Neoplasms Carnitine Palmitoyltransferase I Cell Death Cell Survival Cells Ceramides Cholesterol Clinical Clinical Research Combined Modality Therapy Data Dose Down-Regulation Energy Metabolism Enzymes Fatty Acids Foundations Gene Expression Gene Mutation Genes Genus Hippocampus Glioblastoma Glycolysis Goals Growth Homeostasis In Vitro Isotretinoin Laboratories Lipids Malignant Neoplasms Measures Mediating Mitochondria Molecular Nuclear Receptors Outcome Patients Pharmaceutical Preparations Phospholipids Play Primary Brain Neoplasms Production Prognosis Regulation Reporting Resistance Resistance development Role SRE-1 binding protein Sampling Solid Neoplasm Testing Tissues Tretinoin Tumor Promotion Tumor Tissue cancer cell clinically relevant cohort efficacy evaluation endoplasmic reticulum stress fatty acid oxidation gene synthesis improved in vivo insight lipid biosynthesis lipid metabolism lipidomics metabolomics neoplastic cell novel novel strategies oxidation pharmacologic rapid growth resistance mechanism response screening synergism transcription factor tumor tumor growth uptake

项目摘要

ABSTRACT Glioblastoma (GBM) is the most common primary brain tumor and one of the most lethal of all cancers. The main challenge in treating GBM is the quickly developing resistance to all kinds of treatments by tumor cells. Whereas our partial understanding of GBM biology is a major roadblock to elucidate the underlying resistance mechanisms. Our laboratory recently uncovered that GBM greatly alters lipid metabolism to gain sufficient lipids for its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master transcription factor that controls fatty acid synthesis, is highly expressed in GBM and is essential for tumor growth. Our findings were recently validated by multiple groups showing that SREBP-1 is also elevated in various other cancers. However, whether the dramatically altered lipid metabolism facilitates tumor resistance is completely unknown. Moreover, the mechanism that upregulates SREBP-1 expression in cancer cells remains elusive. Interestingly, we recently found that all-trans retinoic acid (ATRA) and 13-cis-RA could significantly reduce the expression of SREBP-1 and lipogenic enzymes in a dose-dependent manner in GBM cells. These retinoic acids are effective drugs in treating acute promyelocytic leukemia and have also been used to treat GBM and other solid tumors, but tumor resistance has been very challenging. To date, both their antitumor and resistance mechanisms remain poorly understood. We examined the expression of their binding partner, retinoic acid nuclear receptor α (RARα) in GBM patient tissues and found it to be highly expressed in tumor tissues and positively correlated with SREBP-1 expression, while inversely associated with poor patient survival. Interestingly, our data further show that 13-cis-RA and ATRA treatment significantly increased the expression of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme shuttling fatty acids into mitochondria for β-oxidation and energy production. Pharmacological inhibition of CPT1A combined with retinoic acid treatment resulted in marked GBM cell death. Together, these novel preliminary data strongly support the hypothesis that 13-cis-RA or ATRA can significantly alter lipid metabolism in GBM and promote fatty acid oxidation to support tumor cell survival and resistance. We further hypothesize that retinoic acid treatment in combination with suppression of SREBP-1 activation or fatty acid oxidation will effectively inhibit GBM growth and overcome tumor resistance. The goal of this study is to identify the previously unreported roles and mechanisms of retinoic acids and RARα in lipid metabolism regulation and GBM growth (Aim 1), and to develop effective combination approaches to target GBM (Aim 2). Completion of this study will uncover the underlying mechanism upregulating SREBP-1 expression and lipogenesis in GBM, provide great insights into understanding the antitumor and resistance mechanisms of retinoic acids, and identify novel strategies to target GBM and overcome retinoic acid resistance.

抽象的胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是所有癌症中最致命的脑肿瘤之一。主治疗GBM的挑战是迅速产生肿瘤细胞对各种治疗的抗性。然而我们对GBM生物学的部分理解是阐明潜在阻力的主要障碍机制。我们的实验室最近发现，GBM大大改变了脂质代谢以获得足够的脂质因为它的快速增长。我们确定了固醇调节元素结合蛋白-1（SREBP-1），控制脂肪酸合成的转录因子在GBM中高度表达，对于肿瘤至关重要生长。我们的发现最近通过多个组验证，表明SREBP-1在各种中也升高其他癌症。但是，脂质代谢的最爱肿瘤耐药性是否发生了巨大改变完全未知。此外，更新癌细胞中SREBP-1表达的机制仍然存在难以捉摸。有趣的是，我们最近发现，全反式视黄酸（ATRA）和13-CIS-RA可以显着在GBM细胞中以剂量依赖性方式降低SREBP-1和脂肪生物的表达。这些视黄酸是治疗急性寄生虫细胞白血病的有效药物，也已用于治疗GBM 和其他实体瘤，但耐肿瘤的抗性非常挑战。迄今为止，他们的抗肿瘤和抵抗机制仍然很少理解。我们检查了其结合伙伴的表达 GBM患者组织中的酸核接收器α（RARα），发现它在肿瘤组织和与SREBP-1表达呈正相关，而与患者的生存不良成反比。有趣的是，我们的数据进一步表明，13-CIS-RA和ATRA处理显着增加了肉碱棕榈转移酶1A（CPT1A），一种键酶将脂肪酸穿梭到线粒体中以进行β-氧化和能源生产。药理学抑制CPT1A与视黄酸治疗相结合导致明显的GBM细胞死亡。这些新颖的初步数据共同支持了13-CIS-RA的假设或ATRA可以显着改变GBM中的脂质代谢，并促进脂肪酸氧化以支持肿瘤细胞生存和抵抗。我们进一步假设视黄酸治疗结合了抑制 SREBP-1激活或脂肪酸氧化将有效抑制GBM的生长并克服肿瘤耐药性。这项研究的目的是确定视黄酸和RARα的先前未报告的作用和机制在脂质代谢调节和GBM增长中（AIM 1），并开发有效的组合方法目标GBM（AIM 2）。这项研究的完成将揭示上调SREBP-1的基本机制 GBM中的表达和脂肪形成，为理解抗肿瘤和抗性提供了很好的见解视黄酸的机制，并确定靶向GBM并克服视黄酸耐药性的新型策略。