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: 10155452
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10155452
• 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; Clinical; Coupled; Cysteine; Cystine; Data; Development; Diagnosis; Disease; Elements; Endothelial Cells; Epidemiology; Equilibrium; Gene Expression; Genes; Glutamates; Glutathione; Goals; Growth; HIV; HIV Infections; HIV-1; Heme; 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; Proteins; Research; Resistance; Resources; Skin; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Viral; Virus; Visceral; Western World; addiction; antiporter; antiretroviral therapy; base; cell growth; 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; 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.

项目概要 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。发生 KS 的常见因素包括致癌性疱疹病毒卡波西感染 肉瘤疱疹病毒（KSHV/HHV8）和免疫失调。虽然 ART 降低了 KS 的发生率 在西方世界，它仍然是全世界最常见的与艾滋病相关的恶性肿瘤。不断增长的 KS 知识 改善了治疗选择，但它仍然是一种无法治愈的癌症，导致显着的发病率和死亡率， 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疗法 与常规疗法联合使用或代替常规疗法。 KSHV 深刻改变了转录组 宿主细胞，显着影响多种细胞稳态和适应性途径的功能。 对这些途径的研究已经确定了许多成分作为 KS 的潜在治疗靶点， 但我们对病毒与宿主相互作用的了解存在巨大差距，阻碍了进展。在这个应用程序中，我们重点关注 特别是受 KSHV 感染影响的两条重要且相互关联的宿主细胞途径，铁 代谢和抗氧化途径，并研究为什么 KSHV 感染的 EC 对铁死亡具有抵抗力，这是一种 铁依赖性形式的受调节细胞死亡，其特征是 ROS 积累和致命的氧化 对磷脂的损害。为了支持异常生长，肿瘤细胞通常需要更高的铁，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 表明 KS 在这方面与其他癌症相似，并直接表明 KSHV 与该表型有关。尤其， 淋巴内皮细胞（LEC）的体外感染导致铁代谢基因失调， 铁反应性生长表型的发展。虽然铁会促进肿瘤生长，但铁成瘾会导致 悖论：如何维持氧化还原稳态并抵抗铁死亡？许多肿瘤细胞达到这种平衡 具有增强的抗氧化反应，包括激活铁死亡抑制途径以抵抗致命 脂质过氧化。我们的数据显示 KSHV 上调 SLC7A11 (xCT)，SLC7A11 (xCT) 是经典的关键启动子 xCT/GSH/GPX4 铁死亡抑制途径，并且 KSHV 感染的细胞特别容易受到 当 xCT 被抑制时，铁死亡。此外，KSHV 上调新发现的抗铁死亡基因， 铁死亡抑制蛋白 1 (FSP1)，通过独立的 CoQ 依赖性途径发挥作用 抑制铁死亡，从而为选择性消除 KSHV 感染细胞提供替代靶点。在 在此应用中，我们将测试 KSHV 重新编程宿主细胞代谢的创新前提，以获得 铁促进生长并激活两个独立但互补的铁死亡抑制途径。我们 假设这种重编程虽然对肿瘤生长和存活很重要，但创造了独特的点 可以进行治疗性利用的脆弱性。