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 Kaposi肉瘤（KS）是一种多灶性血管增生性肿瘤，影响皮肤，口服粘膜，淋巴结和 内脏器官。 KS发育的常见因素包括感染癌症的疱疹病毒Kaposi 肉瘤疱疹病毒（KSHV/HHV8）和免疫放松管制。虽然艺术减少了KS的发病率 西方世界，它仍然是全世界最常见的艾滋病相关的恶性肿瘤。越来越多的KS知识 已经改善了治疗选择，但仍然是无法治愈的癌症，导致了明显的发病率和死亡率， 特别是在资源有限的地区。因此，迫切需要有效且负担得起的新颖疗法 用于与常规疗法结合或代替常规疗法。 KSHV深刻改变了 宿主细胞显着影响多个细胞体内稳态和自适应途径的功能。 对这些途径的询问已确定许多组件是KS的潜在治疗靶标 但是，我们对病毒宿主相互作用的了解的差距很大。在此应用程序中，我们集中于 特别是在受KSHV感染影响的两个重要且相互连接的宿主细胞途径上 代谢和抗氧化剂途径，并研究了为什么感染KSHV的EC对铁毒性具有抵抗力，一种 铁依赖性的调节细胞死亡形式，其特征是ROS的积累和致命的氧化 对磷脂的损害。为了支持异常生长，肿瘤细胞通常具有更高的铁需求，即 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 建议KS在这方面类似于其他癌症，并在此表型中直接暗示KSHV。尤其， 淋巴内皮细胞（LEC）的体外感染导致铁代谢基因和 铁响应性生长表型的发展。铁燃料肿瘤生长时，铁成瘾呈现A 悖论：如何维持氧化还原稳态并抵抗铁毒性死亡？许多肿瘤细胞达到了这种平衡 具有增强的抗氧化剂反应，包括激活抑制致命的抑制铁的抑制途径 脂质过氧化。我们的数据表明，KSHV上调SLC7A11（XCT），这是规范的关键发起者 XCT/GSH/GPX4铁毒剂抑制途径，并且受KSHV感染的细胞非常容易受到影响 抑制XCT时的铁毒性死亡。此外，KSHV上调了新识别的抗肿瘤基因， 铁凋亡抑制蛋白1（FSP1），通过独立的COQ依赖性，通往的途径发挥作用 抑制铁毒性，因此为选择性消除KSHV感染的细胞提供了替代靶标。在 该应用程序，我们将测试KSHV重编程宿主细胞代谢的创新前提 铁进行生长并激活两个独立但互补的抑制途径。我们 假设这种重编程虽然对肿瘤生长和生存很重要，却创造了独特的点 可以利用治疗的脆弱性。