Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma

多发性骨髓瘤中极长链脂肪酸生物合成的调控和功能

• 批准号: 10441549
• 负责人: Mikhail Nikiforov
• 金额: $ 38.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441549
• 关键词: Acids; Adrenoleukodystrophy; Affect; Anabolism; Antineoplastic Agents; Aryl Hydrocarbon Receptor; Binding; Blood; Bortezomib; Cell Survival; Cell membrane; Cells; Ceramides; Cessation of life; Chromosomal translocation; Coenzyme A; Data; Disease; Drug resistance; Endoplasmic Reticulum; Enzymes; Fatty Acids; Genes; Genetic Transcription; Glycerol; Golgi Apparatus; Hematologic Neoplasms; Homeostasis; Hydro-Lyases; Immunoglobulin G; Immunoglobulins; Inherited; Intervention; Lipids; Lorenzo' s oil; Maintenance; Malignant Neoplasms; Mediating; Membrane; Membrane Lipids; Messenger RNA; Metabolic; Multiple Myeloma; Mus; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Plasma; Plasma Cells; Play; Predisposition; Production; Property; Proteasome Inhibitor; Protein Export Pathway; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Regulation; Reporting; Resistance; Resistance development; Risk; Role; Signal Transduction; Sphingolipids; Testing; Therapeutic Effect; Time; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Very Long Chain Fatty Acid; Xenograft procedure; clinically relevant; efficacy evaluation; endoplasmic reticulum stress; enzyme biosynthesis; experimental study; fatty acid biosynthesis; lipid metabolism; mRNA Expression; mouse model; novel; novel strategies; overexpression; pharmacologic; physical property; response; screening; synergism; therapy resistant; transcription factor

Multiple Myeloma (MM) is a plasma cell disorder that accounts for ~10% of all hematologic malignancies. Due to high production of IgG in endoplasmic reticulum (ER), MM cells continuously undergo ER stress which is considered an “Achille’s heel” of the disease. This feature makes MM susceptible to the agents that exacerbate ER stress, such as proteasome inhibitor bortezomib. Yet, currently MM is incurable for most patients due to rapidly emerging resistance to proteasome inhibitors. Therefore, identification of novel anti-MM drugs and targets is of high importance. Conversely, an increase in protein export from ER is a part of the adaptive response to ER stress. In the current application, we propose a novel clinically relevant pathway controlling ER homeostasis and resistance to bortezomib in MM via modulation of sphingolipid composition of the ER membrane. Our preliminary data suggest that such modulation affects ER-to-Golgi transport, ER homeostasis and ultimately MM cell viability. Furthermore, we identified 3-hydroxyacyl-CoA dehydratases (HACD3), an enzyme involved in the biosynthesis of very long fatty acids (VLCFA), as an important regulator of ER-to-Golgi export and ER homeostasis. Importantly, HACD3 mRNA levels were increased during MM progression and in MM cells from MM patients refractory to bortezomib-containing therapy. Therefore, in Specific Aim 1, we will functionally characterize mechanisms underlying VLCFA-dependent regulation of ER homeostasis and characterize enzymes upstream and downstream of HACD3 responsible for such regulation. In Specific Aim 2, we will identify mechanisms regulating HACD3 mRNA expression in MM cells. In Specific Aim 3, we will evaluate the efficacy of pharmacological suppression of VLCFAs in MM mouse models.

多发性骨髓瘤（MM）是一种浆细胞疾病，约占所有血液恶性肿瘤的10%。 由于内质网（ER）中IgG的高产量，MM细胞持续经历ER应激， 被认为是这种疾病的“致命伤”这一特点使MM容易受到加剧病情的药物的影响。 ER应激，如蛋白酶体抑制剂硼替佐米。然而，目前MM对于大多数患者是不可治愈的， 对蛋白酶体抑制剂迅速产生耐药性。因此，新型抗MM药物的鉴定和 目标非常重要。 相反，ER蛋白质输出的增加是对ER应激的适应性反应的一部分。在 目前的应用，我们提出了一种新的临床相关的途径控制ER稳态和阻力 通过调节ER膜的鞘脂组成，在MM中转化为硼替佐米。我们的初步数据 表明这种调节影响ER到高尔基体的转运、ER体内平衡和最终MM细胞活力。 此外，我们鉴定了3-羟酰基-CoA脱氢酶（HACD 3），一种参与生物合成的酶， 长链脂肪酸（VLCFA），作为ER向高尔基体输出和ER稳态的重要调节剂。 重要的是，在MM进展期间和MM患者的MM细胞中，HACD 3 mRNA水平增加 对含硼替佐米的治疗无效。 因此，在具体目标1中，我们将从功能上描述VLCFA依赖性 ER稳态的调节，并表征HACD 3上游和下游的酶， 这样的规定。在具体目标2中，我们将确定MM细胞中调节HACD 3 mRNA表达的机制。 在具体目标3中，我们将评价VLCFA在MM小鼠模型中的药理学抑制疗效。