Acyl-CoA synthetase ACSVL3 in Malignant Glioma: Metabolism and Oncogenic Cellular

恶性胶质瘤中的酰基辅酶 A 合成酶 ACSVL3：代谢和致癌细胞

• 批准号: 8463259
• 负责人: Paul A. WATKINS
• 金额: $ 33.31万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463259
• 关键词: 1,2-diacylglycerol; Accounting; Adult; Affect; Apoptosis; Appearance; Autophagocytosis; Behavior; Brain Neoplasms; Cell Line; Cell Proliferation; Cells; Cellular Membrane; Childhood; Coenzyme A; Coenzyme A Ligases; Data; Diglycerides; Environment; Enzymes; Event; Family; Family member; Fatty Acids; Glioma; Growth; Histologic; Human; In Vitro; Knowledge; Lipids; Malignant - descriptor; Malignant Glioma; Mediating; Membrane; Membrane Lipids; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Neuroglia; Normal Cell; Oncogenic; PTEN gene; Pathway interactions; Phenotype; Phosphatidylinositols; Phospholipase; Phospholipase C; Phosphorylation; Phosphotransferases; Population; Pre-Clinical Model; Proteins; RNA Interference; Reaction; Receptor Protein-Tyrosine Kinases; Refractory; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Specificity; Structure; Therapeutic; Translating; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cell growth regulation; fatty acid metabolism; glioma cell line; in vivo; knock-down; lipid metabolism; malignant phenotype; novel; novel therapeutic intervention; overexpression; rapid growth; research study; second messenger; subcutaneous; therapeutic target; tumor; tumor growth; tumorigenesis

Malignant glioma accounts for a significant percentage of brain tumors. As these tumors are typically refractory to treatment, there is a need for new and novel therapeutic approaches. Levels of ACSVL3, an enzyme of fatty acid (FA) metabolism, were found to be highly upregulated in human malignant gliomas and were induced by oncogenic receptor tyrosine kinase (RTK) signaling in cultured glioma cells. ACSVL3 is one of 26 acyl-CoA synthetases (ACS) that "activate" FAs for their participation in biosynthetic, degradative, and regulatory downstream metabolic pathways. Rapid tumor growth requires high rates of membrane lipid synthesis; these lipids also have key functions in oncogenic cytoplasmic signaling. Using a well-established preclinical model of human glioma, we found that ACSVL3 knockdown (KD) using RNA interference decreased the in vitro malignant phenotype of human glioma cells. We established a correlation between ACSVL3 expression and tumorigenesis in glioma xenografts in vivo. We further established a relationship between ACSVL3 expression and oncogenic second messenger signaling via the phosphatidyl inositol-3 kinase (PI3K)/Akt and phospholipase c-¿ (PLC-¿)/diacylglycerol (DAG) pathways. We hypothesize that ACSVL3 generates specific FA-CoA products that influence oncogenesis by (i) generating specific structural lipids (ii) altering lipids involved directly in cell signaling, or (iii) altering lipids involved in membrane interactions with specific oncogenic signaling proteins. Based on our preliminary findings, we also hypothesize that targeting ACSVL3 will be of therapeutic value in treating malignant glioma, and propose the following Specific Aims: (1) To identify the consequences of ACSVL3 depletion on the in vitro phenotype of human glioma cell lines, (2) To identify the consequences of ACSVL3 depletion on lipid metabolism in malignant glioma cells, (3) To elucidate how ACSVL3 KD alters signal transduction in malignant glioma cells, and (4) To determine how ACSVL3 depletion inhibits glioma tumorigenicity. In Aim 1 we will investigate cell proliferation, apoptosis, and autophagy in control and KD human glioma cells to determine the specificity for ACSVL3 in oncogenesis. These studies will also be extended to other glioma models that may prove useful in subsequent Aims, such as cell lines that endogenously express the tumor suppressor PTEN. The function of ACSVL3 in lipid metabolism is not known for either normal or cancer cells. Aim 2 proposes studies to fill this gap in knowledge that will also identify lipid pathways that correlate with the malignant phenotype. In Aim 3, detailed analyses of the PI3K/Akt and PLC-¿/ DAG signaling pathways in control and ACSVL3 KD glioma cells will be carried out. In Aim 4, effects of ACSVL3 KD on in vivo tumorigenesis, alterations in lipid metabolism, and RTK signaling will be explored, both in subcutaneous and in intracranial xenografts. The results of these studies will establish the mechanistic basis for ACSVL3 upregulation in glioma, pinpoint the role of this enzyme in oncogenic RTK signaling and lipid metabolism, and validate the therapeutic potential of targeting this protein in malignant glioma.

恶性神经胶质瘤在脑肿瘤中占很大比例。因为这些肿瘤通常是难治性的

项目成果

Very long-chain acyl-CoA synthetase 3 mediates onco-sphingolipid metabolism in malignant glioma.

• DOI: 10.18103/mra.v9i5.2433
• 发表时间: 2021-05
• 期刊: Medical research archives
• 作者: E. Kolar;Xiaohai Shi;Emily M. Clay;A. Moser;B. Lal;R. Nirujogi;A. Pandey;V. Bandaru;J. Laterra;Z. Pei;P. Watkins