Citrulline-urea cycle in KSHV cellular transformation

KSHV 细胞转化中的瓜氨酸-尿素循环

• 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
• 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

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.

卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）和其他几种恶性肿瘤的病原体。我们发现，与大多数其他类型的癌细胞不同，KSHV转化的细胞不依赖于葡萄糖和有氧糖酵解，并且有氧糖酵解水平降低。相反，KSHV转化的细胞对谷氨酰胺上瘾。更令人惊讶的是，谷氨酰胺主要用于合成核苷酸和氨基酸。为了维持代谢流并清除有毒产物，KSHV通过上调关键限速代谢酶乙酰氨基琥珀酸合酶1（ASS 1）来劫持瓜氨酸-尿素循环。值得注意的是，ASS 1对于KSHV转化细胞的增殖和存活至关重要，瓜氨酸-尿素循环的上调通过诱导一氧化氮进一步提供了重要的STAT 3致癌信号。我们的假设是，KSHV编码特定的基因来劫持瓜氨酸-尿素循环，以支持KSHV转化细胞的增殖和存活，因此靶向该途径可有效治疗KSHV诱导的肿瘤。我们已经开发了KSHV诱导的细胞转化和肿瘤发生的有效模型、KSHV转化的细胞的三维（3D）培养模型以及先进的代谢谱分析和追踪技术，所有这些对于测试这种新的假设都特别有用。我们将研究ASS 1和瓜氨酸-尿素循环在维持代谢流、清除毒性产物和激活STAT 3通路以支持KSHV诱导的细胞转化中的重要作用（目的1）;确定ASS 1和活跃的瓜氨酸-尿素循环激活STAT 3通路以支持KSHV诱导的细胞转化的机制（目的2）;确定KSHV上调ASS 1和劫持瓜氨酸-尿素循环的机制（目标3）;并确定瓜氨酸-尿素循环中靶向关键酶治疗KSHV诱导的肿瘤发生的治疗潜力（目标4）。拟议的项目是非常重要的，因为它将测试一个新的假设KSHV操纵的关键细胞代谢途径使用多学科的创新方法和模型系统。我们期望该项目的完成将导致识别新的癌症驱动因素和KSHV诱导的癌症的脆弱性，这可以为开发新的疗法提供科学依据。