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一种。治疗 GBM 的挑战是肿瘤细胞对各种治疗的快速发展的耐药性。我们对 GBM 生物学的部分了解是阐明潜在阻力的主要障碍我们的实验室最近发现 GBM 极大地改变脂质代谢以获得足够的脂质。我们发现甾醇调节元件结合蛋白-1 (SREBP-1) 是其快速生长的关键。控制脂肪酸合成的转录因子，在 GBM 中高表达，对于肿瘤至关重要我们的研究结果最近得到了多个小组的验证，表明 SREBP-1 在各种疾病中也有所升高。然而，脂质代谢的显着改变是否有助于肿瘤抵抗。此外，上调癌细胞中SREBP-1表达的机制仍然完全未知。令人难以捉摸的是，我们最近发现全反式视黄酸（ATRA）和 13-cis-RA 可以显着。以剂量依赖性方式降低 GBM 细胞中 SREBP-1 和脂肪生成酶的表达。视黄酸是治疗急性早幼粒细胞白血病的有效药物，也已用于治疗GBM 和其他实体瘤，但迄今为止，它们的抗肿瘤和抗肿瘤耐药性都非常具有挑战性。我们对它们的结合伙伴视黄酸的表达仍知之甚少。 GBM 患者组织中的酸性核受体 α (RARα) 被发现在肿瘤组织中高表达与 SREBP-1 表达呈正相关，而与患者较差的生存率呈负相关。暗示，我们的进一步数据表明 13-cis-RA 和 ATRA 处理显着增加了肉碱棕榈酰转移酶 1A (CPT1A)，一种将脂肪酸运送到线粒体进行 β-氧化的关键酶 CPT1A 的药理学抑制与视黄酸治疗相结合导致。这些新的初步数据共同有力地支持了 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我们进一步寻求将视黄酸治疗与抑制相结合。 SREBP-1激活或脂肪酸氧化将有效抑制GBM生长并克服肿瘤耐药性。本研究的目的是确定以前未报道的视黄酸和 RARα 的作用和机制脂质代谢调节和 GBM 生长（目标 1），并开发有效的组合方法目标 GBM（目标 2）。完成本研究将揭示上调 SREBP-1 的潜在机制。 GBM 中的表达和脂肪生成，为了解抗肿瘤和耐药性提供了重要见解视黄酸的机制，并确定针对 GBM 和克服视黄酸耐药性的新策略。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

DOI：
10.1016/j.cmet.2020.06.002
发表时间：
2020-06-09
期刊：
Cell metabolism
影响因子：
29
作者：
Xiang Cheng;F. Geng;Meixia Pan;Xiaoning Wu;Y. Zhong;Chunyan Wang;Zhihua Tian;Chunming Cheng;Rui Zhang;V. Puduvalli;C. Horbinski;X. Mo;Xianlin Han;A. Chakravarti;Deliang Guo
通讯作者：
Deliang Guo

Glutamine-released ammonia acts as an unprecedented signaling molecule activating lipid production.

谷氨酰胺释放的氨充当前所未有的信号分子，激活脂质产生。

DOI：
发表时间：
2023-03
期刊：
影响因子：
6.8
作者：
Cheng, Chunming;Kelsey, Scott;Guo, Deliang
通讯作者：
Guo, Deliang

DGAT1 protects tumor from lipotoxicity, emerging as a promising metabolic target for cancer therapy.

DGAT1 可保护肿瘤免受脂毒性，成为癌症治疗的一个有前景的代谢靶点。

DOI：
发表时间：
2020-09-08
期刊：
影响因子：
2.1
作者：
Cheng, Xiang;Geng, Feng;Guo, Deliang
通讯作者：
Guo, Deliang

Lipid Droplets Maintain Energy Homeostasis and Glioblastoma Growth via Autophagic Release of Stored Fatty Acids.

脂滴通过储存脂肪酸的自噬释放来维持能量稳态和胶质母细胞瘤生长。

DOI：
发表时间：
2020-10-23
期刊：
影响因子：
5.8
作者：
Wu, Xiaoning;Geng, Feng;Cheng, Xiang;Guo, Qiang;Zhong, Yaogang;Cloughesy, Timothy F;Yong, William H;Chakravarti, Arnab;Guo, Deliang
通讯作者：
Guo, Deliang

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.

SREBP-1 上调脂肪吞噬以维持脑肿瘤细胞中的胆固醇稳态。

DOI：
发表时间：
2023-07-25
期刊：
影响因子：
8.8
作者：
Geng, Feng;Zhong, Yaogang;Su, Huali;Lefai, Etienne;Magaki, Shino;Cloughesy, Timothy F;Yong, William H;Chakravarti, Arnab;Guo, Deliang
通讯作者：
Guo, Deliang