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Identifying SREBP-1 activation mechanism in glioblastoma and its new role in regulating glutamine metabolism

鉴定胶质母细胞瘤中SREBP-1的激活机制及其在调节谷氨酰胺代谢中的新作用

基本信息

批准号：
10553204
负责人：
Deliang Guo
金额：
$ 35.95万
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：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553204
关键词：
18F-Glutamine Adult Affect Affinity Amino Acid Transporter Ammonia Binding Binding Sites Biology Brain Cells Cholesterol Clinical Data Dissociation Endoplasmic Reticulum Enzymes Essential Amino Acids Exhibits Genes Genetic Transcription Glioblastoma Glucose Glutamates Glutaminase Glutamine Golgi Apparatus Growth In Vitro Insulin Isoleucine Knowledge Laboratories Leucine Link Lipids Malignant Neoplasms Measures Mediating Membrane Metabolic Metabolism Modeling Molecular Mutate N-terminal Normal Cell Outcome Pathway interactions Patients Play Positron-Emission Tomography Primary Brain Neoplasms Process Prognosis Promoter Regions Protein Conformation Proteins Proteolysis Publishing Reporting Repression Role SCAP protein SRE-1 binding protein Sampling Site Therapeutic Tumor Promotion Tumor Tissue Valine Withdrawal Xenograft Model alpha ketoglutarate amino acid metabolism cancer cell glycosylation improved in vivo insight lipid biosynthesis lipid metabolism novel prevent programs promoter rapid growth synergism trafficking transcription factor tumor growth uptake

项目摘要

ABSTRACT Glioblastoma (GBM) is the most lethal primary brain tumor, and its prognosis has no significantly improved in the past two decades. It is urgent to identify effective strategies to treat GBM, but our only partial understanding of GBM biology significantly hinders this progress. Our laboratory has long focused on understanding GBM biology and recently demonstrated that GBM reprograms lipid metabolism to support its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master transcription factor regulating lipid synthesis, is highly activated in GBM and is essential for tumor growth. However, the molecular mechanism activating SREBP-1 and lipogenesis in cancer cells remains unclear. Moreover, whether the highly activated SREBP-1 plays new roles in malignancy is unknown. In normal cells, SREBP activation is strongly repressed by Insulin-induced gene (Insig), an endoplasmic reticulum (ER)-anchored protein. It binds to the SREBP transporter, SREBP-cleavage protein (SCAP), preventing SREBP ER-to-Golgi translocation and subsequent activation. Thus, the first key step for SREBP-1 activation is SCAP dissociation from Insig. How cancer cells are able to release the tight repression of Insig on SCAP to promote high levels of SREBP- 1 activation remains unanswered. We recently found that glucose-mediated N-glycosylation stabilizes SCAP. Interestingly, our new preliminary data showed that in the absence of glutamine, SREBP-1 failed to be cleaved, although SCAP remained glycosylated. Inhibiting glutamine conversion to glutamate and ammonia by suppressing glutaminase (GLS) markedly reduced SREBP-1 cleavage. These data strongly suggest that glutamine plays a critical role in SREBP-1 activation. Interestingly, expressing the active N-terminal form of SREBP-1 in GBM cells significantly enhanced glutamine uptake. Analysis of GBM patient samples showed that the glutamine transporter, SLC1A5, is highly expressed in tumor tissues and is inversely correlated with patient survival. Promoter analysis showed multiple putative SREBP-1 binding sites in the SLC1A5 promoter region. Based on these new preliminary data and our published studies, we hypothesize that SCAP dissociation from Insig is activated by glutamine-derived metabolites, leading to SREBP-1 activation; in turn, activated SREBP-1 transcriptionally upregulate the expression of SLC1A5, resulting in a feedforward loop to increase glutamine uptake and lipid synthesis to promote GBM growth. In this study, we will identify the molecular mechanism activating SREBP-1 and lipogenesis by glutamine in GBM in Aim 1, and reveal the new role of SREBP-1 in regulating glutamine metabolism in Aim 2. We will further examine whether combining inhibition of SREBP-1 together with SLC1A5 or GLS suppression provides strong synergy to inhibit GBM growth (Aim 2). Completion of this study will significantly advance our understanding of GBM biology and metabolism rewiring, and provide promising approaches for GBM therapy.

摘要