Citrulline-urea cycle in KSHV cellular transformation

KSHV 细胞转化中的瓜氨酸-尿素循环

基本信息

批准号：
10634838
负责人：
Shou-Jiang Gao
金额：
$ 54.05万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634838
关键词：
3-Dimensional Abbreviations Acquired Immunodeficiency Syndrome Amino Acids Animal Model Biological Models Cell Culture Techniques Citric Acid Cycle Citrulline Consumption Development Ensure Enzyme Inhibition Enzymes Genes Glucose Glutamine Goals Herpesviridae Infections Human Human Herpesvirus 8 Kaposi Sarcoma Malignant Neoplasms Mediating Mesenchymal Stem Cells Metabolic Metabolic Pathway MicroRNAs Modeling Morbidity - disease rate Multicentric Angiofollicular Lymphoid Hyperplasia NOS2A gene Nitric Oxide Nitrogen Nucleotides Oncogenic Pathway interactions Patients Prevention Proliferating Proteins Regulation Role STAT3 gene Signal Induction Signal Transduction Signaling Molecule Societies Technology Testing Therapeutic Up-Regulation Warburg Effect Work aerobic glycolysis argininosuccinate synthase cancer cell cancer type carcinogenesis cell transformation effectiveness evaluation expectation innovation knockout gene metabolic profile metaplastic cell transformation mortality multidisciplinary new therapeutic target novel novel therapeutics nucleotide metabolism pharmacologic primary effusion lymphoma therapeutic target tumor tumorigenesis urea cycle

项目摘要

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causal agent of Kaposi’s sarcoma (KS) and several other malignancies. We have discovered that, unlike most other types of cancer cells that are addicted to glucose and aerobic glycolysis, KSHV-transformed cells do not depend on glucose and have a reduced level of aerobic glycolysis. Instead, KSHV-transformed cells are addicted to glutamine. More surprisingly, glutamine is primarily shunted to the syntheses of nucleotides and amino acids. To maintain the metabolic flow and clear the toxic products, KSHV hijacks the citrulline-urea cycle by upregulating the key rate-limiting metabolic enzyme argininosuccinate synthase 1 (ASS1). Significantly, ASS1 is essential for the proliferation and survival of KSHV- transformed cells and upregulation of the citrulline-urea cycle further provides an essential STAT3 oncogenic signal by inducing nitric oxide. Our hypothesis is that KSHV encodes specific gene(s) to hijack the citrulline-urea cycle to support the proliferation and survival of KSHV-transformed cells, and hence targeting this pathway is effective for treating KSHV-induced tumors. We have developed an efficient model of KSHV-induced cellular transformation and tumorigenesis, three-dimensional (3D) culture models KSHV- transformed cells, and advanced metabolic profiling and tracing technologies, all of which are particularly useful for testing this novel hypothesis. We will examine the essential roles of ASS1 and citrulline-urea cycle for maintaining metabolic flow, clearing toxic products and activating STAT3 pathway to support KSHV-induced cellular transformation (Aim 1); determine the mechanism by which ASS1 and active citrulline-urea cycle activate the STAT3 pathway to support KSHV-induced cellular transformation (Aim 2); determine the mechanism by which KSHV upregulates ASS1 and hijacks the citrulline-urea cycle (Aim 3); and determine the therapeutic potential of targeting key enzymes in the citrulline-urea cycle for treating KSHV-induced tumorigenesis (Aim 4). The proposed project is highly significant as it will test a novel hypothesis of KSHV manipulation of a key cellular metabolic pathway using multidisciplinary innovative approaches and model systems. It is our expectations that accomplishment of this project will lead to the identification of novel cancer drivers and vulnerabilities of KSHV-induced cancers, which could provide a scientific basis for developing novel therapies.

卡波西（Kaposi）与肉瘤相关的疱疹病毒（KSHV）是卡波西（Kaposi）肉瘤（KS）和其他几个恶性肿瘤的因果特工。我们发现，与大多数其他类型的癌细胞添加到葡萄糖和有氧糖酵解中不同，KSHV转换的细胞不依赖葡萄糖，并且有氧糖溶解水平降低。相反，将KSHV转换的细胞添加到谷氨酰胺中。更令人惊讶的是，谷氨酰胺主要分解为核动肽和氨基酸的合成。为了维持代谢流并清除有毒产物，KSHV通过上调限制限制速率的代谢酶ArginInoscinate合成酶1（ASS1）来劫持瓜氨酸 - 尿素周期。值得注意的是，ASS1对于KSHV转化的细胞的增殖和存活至关重要，瓜氨酸尿素周期的上调进一步提供了通过诱导的一氧化氮信号的必要的STAT3致癌信号。我们的假设是，KSHV编码特定的基因来劫持瓜氨酸 - 尿素周期以支持KSHV转换的细胞的增殖和存活，因此靶向该途径有效治疗KSHV诱导的肿瘤。我们已经开发了一个有效的KSHV诱导的细胞转化和肿瘤发生，三维（3D）培养模型KSHV转化的细胞以及先进的代谢分析和追踪技术的模型，所有这些模型对于测试这一新假设特别有用。我们将研究ASS1和Citrullline-rea循环在维持代谢流，清除有毒产物并激活STAT3途径以支持KSHV诱导的细胞转化的基本作用（AIM 1）；确定ASS1和主动citrullline-rea循环激活STAT3途径以支持KSHV诱导的细胞转化的机制（AIM 2）；确定KSHV上调ASS1并劫持柑橘类尿液周期的机制（AIM 3）；并确定靶向瓜氨酸 - 尿素周期中关键酶以治疗KSHV诱导的肿瘤发生的治疗潜力（AIM 4）。提出的项目非常重要，因为它将使用多学科创新方法和模型系统测试KSHV操纵KSHV操纵的新假设。我们期望该项目的完成将导致对新型癌症驱动因素的识别和KSHV引起的癌症的脆弱性，这可以为开发新型疗法提供科学基础。