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.

项目总结 摘要卡波西肉瘤是一种多灶性血管增生性肿瘤，累及皮肤、口腔粘膜、淋巴结和皮肤。 内脏器官。KS发生的常见因素包括感染致癌性疱疹病毒Kaposi 肉瘤疱疹病毒(KSHV/HHV8)与免疫松弛虽然抗逆转录病毒治疗降低了KS在 在西方世界，它仍然是世界上最常见的与艾滋病相关的恶性肿瘤。不断增长的KS知识 已经改进了治疗方案，但它仍然是一种无法治愈的癌症，会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。 与传统疗法结合使用或替代传统疗法使用。KSHV深刻改变了KSHV的转录组 宿主细胞，显著影响多条细胞内稳态和适应性通路的功能。 对这些途径的询问已经确定了一些成分作为KS的潜在治疗靶点， 但是，我们对病毒-宿主相互作用的了解存在重大差距，阻碍了进展。在此应用程序中，我们关注 尤其是受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，并调查感染KSHV的EC对铁下垂耐药的原因。 铁依赖形式的调节性细胞死亡，其特征是ROS的积累和致命的氧化 对磷脂的破坏。为了支持异常生长，肿瘤细胞通常有更高的铁需求，这是 通过调节铁的吸收、利用和储存的基因表达的改变而得到满足。我们的初步数据 提示KS在这方面与其他癌症相似，并直接与KSHV的这种表型有关。值得注意的是， 淋巴内皮细胞(LEC)体外感染导致铁代谢基因和 铁反应生长表型的形成。虽然铁促进了肿瘤的生长，但铁成瘾是一种 悖论：如何维持氧化还原动态平衡和抵抗铁腐症死亡？许多肿瘤细胞达到这种平衡 具有增强的抗氧化反应，包括激活铁下垂抑制通路以抵抗致命的 脂质过氧化。我们的数据表明，KSHV上调了SLC7A11(XCT)，SLC7A11(XCT)是正则基因的关键启动者 XCT/GSH/Gpx4铁下垂抑制通路，以及KSHV感染细胞对 当XCT被抑制时，铁眼性死亡。此外，KSHV还上调了新发现的反铁上链基因， 铁下垂抑制蛋白1(FSP1)，它通过一个独立的、辅酶Q依赖的途径发挥作用，从而 抑制铁下垂，从而为选择性消除KSHV感染的细胞提供了一个替代靶点。在……里面 此次应用，我们将测试KSHV重新编程宿主细胞代谢的创新前提 铁促进生长，并激活两个独立但互补的铁下垂抑制途径。我们 假设这种重新编程，虽然对肿瘤的生长和存活很重要，但创造了 可以在治疗上利用的脆弱性。