KSHV Manipulates Host Iron Metabolism and Ferroptotic Cell Death Pathways, Creating Novel Vulnerability Points for Therapeutic Intervention.

KSHV 操纵宿主铁代谢和铁死亡细胞死亡途径，为治疗干预创造新的脆弱点。

• 批准号: 10617677
• 负责人: ASHLEE V. MOSES
• 金额: $ 35.23万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617677
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Address; Affect; African; Amino Acid Transporter; Amino Acids; Antioxidants; Cancer Etiology; Catalytic Domain; Cell Death; Cells; Cellular Metabolic Process; Cellular biology; Cessation of life; Coupled; Cysteine; Cystine; Data; Development; Diagnosis; Disease; Drug Metabolic Detoxication; Elements; Endothelial Cells; Equilibrium; Gene Expression; Genes; Glutamates; Glutathione; Goals; Growth; HIV; HIV Infections; HIV-1; Heme; Herpesviridae; Homeostasis; Human Herpesvirus 8; Iatrogenic Kaposi' s Sarcoma; Immune; In Vitro; Incidence; Infection; Iron; Kaposi Sarcoma; Knowledge; Limes; Lipid Peroxidation; Lipid Peroxides; Lipids; Lymphatic Endothelial Cells; Malignant Neoplasms; Modeling; Morbidity - disease rate; Oncogenic; Oral mucous membrane structure; Organ; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Persons; Phenotype; Phospholipids; Predisposition; Proteins; Research; Resistance; Resource-limited setting; Skin; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Viral; Virus; Visceral; Western World; addiction; antagonist; antiporter; antiretroviral therapy; cell growth; clinical epidemiology; cofactor; combat; conventional therapy; enzyme substrate; epidemiology study; extracellular; improved; in vivo; innovation; interdisciplinary approach; iron metabolism; lymph nodes; mortality; neoplastic cell; novel; novel therapeutics; overexpression; oxidative damage; prevent; programs; response; therapeutic target; transcriptome; tumor; tumor growth; uptake; virus host interaction

PROJECT SUMMARY Kaposi sarcoma (KS) is a multifocal angioproliferative tumor affecting the skin, oral mucosa, lymph nodes and visceral organs. Common factors for KS development include infection with the oncogenic herpesvirus Kaposi sarcoma herpesvirus (KSHV/HHV8) and immune deregulation. While ART has reduced KS incidence in the Western world, it remains the most common AIDS-associated malignancy worldwide. Growing knowledge of KS has improved treatment options, but it remains an incurable cancer causing significant morbidity and mortality, particularly in resource-limited regions. Thus, there is an urgent need for effective and affordable novel therapies for use in combination with, or instead of, conventional therapies. KSHV profoundly alters the transcriptome of the host cell, significantly influencing the function of multiple cellular homeostatic and adaptive pathways. Interrogation of these pathways has identified a number of components as potential therapeutic targets for KS, but significant gaps in our knowledge of the virus-host interaction hamper progress. In this application, we focus specifically on two important and inter-connected host cell pathways that are influenced by KSHV infection, iron metabolism and the antioxidant pathway, and investigate why KSHV-infected EC are resistant to ferroptosis, an iron-dependent form of regulated cell death that is characterized by accumulation of ROS and lethal oxidative damage to phospholipids. To support abnormal growth, tumor cells typically have a higher iron need, which is satisfied through altered expression of genes regulating iron uptake, utilization and storage. Our preliminary data suggest that KS resembles other cancers in this regard and directly implicate KSHV in this phenotype. Notably, in vitro infection of lymphatic endothelial cells (LEC) results in deregulation of iron metabolism genes and development of an iron-responsive growth phenotype. While iron fuels tumor growth, iron addiction presents a paradox: how to maintain redox homeostasis and resist ferroptotic death? Many tumor cells achieve this balance with an enhanced antioxidant response that includes activation of ferroptosis suppressor pathways to resist lethal lipid peroxidation. Our data show that KSHV upregulates SLC7A11 (xCT), a critical initiator of the canonical xCT/GSH/GPX4 ferroptosis suppressor pathway, and that KSHV-infected cells are uniquely susceptible to ferroptotic death when xCT is inhibited. In addition, KSHV upregulates the newly-identified anti-ferroptotic gene, ferroptosis suppressor protein 1 (FSP1), which functions through an independent, CoQ-dependent, pathway to suppress ferroptosis, thus presenting an alternate target for the selective elimination of KSHV-infected cells. In this application, we will test the innovative premise that KSHV reprograms host cell metabolism both to acquire iron for growth and to activate two independent but complementary ferroptosis suppressor pathways. We hypothesize that this reprogramming, while important for tumor growth and survival, creates unique points of vulnerability that can be therapeutically exploited.

项目摘要 卡波西肉瘤（KS）是一种多灶性血管增生性肿瘤，累及皮肤、口腔粘膜、淋巴结和 内脏器官KS发展的常见因素包括感染致癌疱疹病毒Kaposi 肉瘤疱疹病毒（KSHV/HHV 8）和免疫失调。虽然ART降低了KS的发病率， 在西方世界，它仍然是全球最常见的艾滋病相关恶性肿瘤。知识的增长 已经改善了治疗选择，但它仍然是一种无法治愈的癌症，导致显著的发病率和死亡率， 特别是在资源有限的地区。因此，迫切需要有效和负担得起的新疗法 用于与常规疗法组合使用或代替常规疗法。KSHV深刻地改变了 宿主细胞，显著影响多种细胞稳态和适应性途径的功能。 对这些通路的研究已经确定了许多组分作为KS的潜在治疗靶点， 但我们对病毒-宿主相互作用的认识存在重大差距，阻碍了进展。在这个应用程序中，我们专注于 特别是在受KSHV感染影响的两个重要且相互关联的宿主细胞途径上，铁 代谢和抗氧化途径，并研究为什么KSHV感染的EC对铁亡有抵抗力，以及 铁依赖性形式的受调节的细胞死亡，其特征在于ROS和致死性氧化 对磷脂的损害。为了支持异常生长，肿瘤细胞通常需要更高的铁，这是非常重要的。 通过改变调节铁吸收、利用和储存的基因表达来满足。我们的初步数据 提示KS在这方面类似于其他癌症，并直接暗示KSHV与该表型有关。值得注意的是， 淋巴管内皮细胞（LEC）的体外感染导致铁代谢基因的失调， 铁响应性生长表型的发展。虽然铁燃料肿瘤生长，铁成瘾提出了一个 悖论：如何维持氧化还原平衡和抵抗铁中毒死亡？许多肿瘤细胞达到这种平衡 具有增强的抗氧化反应，包括铁凋亡抑制途径的激活，以抵抗致命的 脂质过氧化我们的数据表明，KSHV上调SLC 7A 11（xCT），这是典型的 xCT/GSH/GPX 4铁凋亡抑制途径，KSHV感染的细胞对 当xCT被抑制时，铁中毒性死亡。此外，KSHV上调新鉴定的抗铁蛋白基因， 铁凋亡抑制蛋白1（FSP 1），其功能通过一个独立的，辅酶Q依赖性，途径， 抑制铁凋亡，从而为选择性消除KSHV感染的细胞提供了替代靶点。在 在这项应用中，我们将测试KSHV重新编程宿主细胞代谢的创新前提， 铁的生长和激活两个独立但互补的铁凋亡抑制途径。我们 假设这种重编程虽然对肿瘤生长和存活很重要，但会产生独特的 可以被利用的弱点