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.

恶性神经胶质瘤占脑肿瘤的很大一部分。由于这些肿瘤通常是难治性的 为了治疗，需要采用新的新型治疗方法。 ACSVL3的水平，脂肪酶 发现在人类恶性神经胶质瘤中酸（FA）代谢高度更新，并被诱导 培养的神经胶质瘤细胞中的致癌受体酪氨酸激酶（RTK）信号传导。 ACSVL3是26个酰基-COA之一 合成酶（ACS）“激活” FAS以参与生物合成，降解和调节性 下游代谢途径。快速肿瘤生长需要高膜脂质合成速率。这些 脂质在致癌细胞质信号传导中也具有关键功能。使用完善的临床前模型 人神经胶质瘤，我们发现使用RNA干扰的ACSVL3敲低（KD）在体外下降 人神经胶质瘤细胞的恶性表型。我们建立了ACSVL3表达与 胶质瘤Xenographographics在体内的肿瘤发生。我们进一步建立了ACSVL3表达之间的关系 通过磷脂酰肌醇-3激酶（PI3K）/AKT和AKT和ONCENIC SECTERD MESSENGER信号传导 磷脂酶C-¿（PLC-）/二酰基甘油（DAG）途径。我们假设ACSVL3会生成特定 通过（i）产生特定结构脂质（II）改变脂质的FA-COA产品 直接参与细胞信号传导，或（iii）改变与特定的膜相互作用涉及的脂质 致癌信号蛋白。根据我们的初步发现，我们还假设针对ACSVL3 治疗恶性神经胶质瘤和提议以下特定目的将具有热价值：（1） 确定ACSVL3部署对人神经胶质瘤细胞系的体外表型的后果，（2）至 确定ACSVL3部署对恶性神经胶质瘤细胞中脂质代谢的后果，（3）阐明 ACSVL3 KD如何改变恶性神经胶质瘤细胞中的信号转导，（4）确定ACSVL3如何 耗竭抑制神经胶质瘤肿瘤性。在AIM 1中，我们将研究细胞增殖，凋亡和自噬 在对照和KD人神经胶质瘤细胞中确定肿瘤发生中ACSVL3的特异性。这些研究 还将扩展到其他可能在后续目标中有用的神经胶质瘤模型，例如细胞系 内源性表达肿瘤抑制剂PTEN。 ACSVL3在脂质代谢中的功能尚不清楚 对于正常或癌细胞。目标2个建议研究以填补这一知识的差距，这也将识别脂质 与恶性表型相关的途径。在AIM 3中，PI3K /AKT和PLC-®的详细分析 / 将执行对照和ACSVL3 KD神经胶质瘤细胞中的DAG信号通路。在AIM 4中，效果 ACSVL3 KD在体内肿瘤发生，脂质代谢的改变和RTK信号的变化都将被探索，两者都将被探索 在皮下和颅内元组学中。这些研究的结果将建立机械基础 对于神经胶质瘤的ACSVL3上调，请指出该酶在致癌RTK信号和脂质中的作用 代谢，并验证靶向这种蛋白质蛋白质的治疗潜力。

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