Hydrogen sulfide functions as a tumor suppressor in glioblastoma

硫化氢在胶质母细胞瘤中充当肿瘤抑制剂

• 批准号: 10656703
• 负责人: CHRISTOPHER Michael HINE
• 金额: $ 51.51万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656703
• 关键词: Acceleration; Adult; Affect; Age; Aging; Attenuated; Biological Availability; Brain; Cell Maintenance; Cell Proliferation; Cells; Chemicals; Clinical; Clinical Trials; Cues; Cysteine Desulfhydrase; Data; Diagnosis; Elderly; Enzymes; Epigenetic Process; FDA approved; Generations; Genetic; Genetically Engineered Mouse; Glioblastoma; Goals; Growth; Human; Hydrogen Sulfide; Hypothyroidism; Immunologic Surveillance; Immunosuppression; Immunotherapy; In Vitro; Intervention; Knock-out; Knockout Mice; Life; Longevity; Maintenance; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Metabolic; Metabolism; Methimazole; Mitochondria; Modeling; Molecular; Nerve Degeneration; Outcome; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Primary Brain Neoplasms; Production; Progression-Free Survivals; Proliferating; Propylthiouracil; Protein S; Proteins; Publishing; Radio; Recurrence; Regulation; Repression; Resistance; Role; Sampling; Signal Transduction; Site; Specimen; Sulfur Amino Acids; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Thyroid Gland; Thyroid Hormones; Time; Tissues; Tumor Burden; Tumor Suppression; Tumor Suppressor Proteins; Visit; age effect; aged; amino acid metabolism; cancer stem cell; clinically relevant; detection assay; dietary; experimental study; hormonal signals; human old age (65+); immune activation; immune function; improved; in vivo; juvenile animal; metabolic fitness; mouse model; multimodality; neoplastic cell; neural; novel; overexpression; patient derived xenograft model; pharmacologic; pre-clinical; prevent; programs; response; self-renewal; standard of care; stem cell population; stem cell self renewal; stem cell survival; sulfhydration; synergism; temozolomide; therapy resistant; treatment strategy; tumor; tumor growth; tumor initiation; tumor microenvironment; tumorigenic

ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM growth and therapeutic resistance are driven by a combination of self-renewing cancer stem cells (CSCs) and an aging- induced tumor-supportive microenvironment. CSCs are regulated by cell intrinsic genetic and epigenetic networks, extrinsic cellular interactions with the surrounding microenvironment, and the interaction between those intrinsic and extrinsic regulatory programs. While multiple molecular mechanisms that drive self-renewal have been identified, the effects of advanced age on CSC maintenance has yet to be explored. Specifically, it is unclear how advanced age alters CSC maintenance and GBM growth. A recently recognized hallmark of advanced age is the shift in sulfur amino acid metabolism that suppresses enzyme-dependent hydrogen sulfide (H2S) generation, signaling, and bioavailability. H2S is a redox-active metabolite that signals through protein S- sulfhydration (R-SSnH) and impacts metabolism, immune activation, and longevity. Its enzymatic production by cystathionine γ-lyase (CGL) is repressed by thyroid hormone (TH). H2S has both pro- and anti-tumorigenic functions that are tumor-type dependent. However, there is limited information on cell intrinsic and tumor microenvironment functions of H2S in GBM. Recently, we modulated H2S levels through dietary and pharmacological interventions and found that H2S functions as a tumor suppressor in GBM and attenuates CSC self-renewal and tumor growth in pre-clinical models. H2S generation and sulfhydration were decreased in human GBM specimens as compared to non-tumor controls. While the data support the hypothesis that H2S functions as a tumor suppressor in GBM, the effects of aging-induced H2S declines on GBM progression and CSCs, and how to reverse this for clinical use, are unexplored. Based on our published findings and new preliminary data, we hypothesize that decreased H2S production during aging promotes CSC initiation, immune suppression, and drives GBM growth but can ultimately be reversed by anti-TH based H2S boosting approaches. We will test this hypothesis through the following aims by integrating our newly developed H2S and sulfhydration detection assays in combination with in vitro and in vivo GBM models that manipulate H2S production via genetic and pharmacological interventions with human samples to provide clinical relevance. Aim 1 tests the hypothesis that aging-induced suppression of CGL-derived H2S accelerates GBM progression. Aim 2 tests the hypothesis that chemically-induced hypothyroidism stimulates CGL to increase systemic and neural H2S production resulting in reduced GBM progression, CSC enrichment, and improved survival in preclinical GBM models. The long-term goal of this project is to interrogate the function of H2S as a GBM tumor suppressor that is lost during aging, while also studying the therapeutic effects of hypothyroid-induced H2S production and signaling to reduce CSC maintenance and immune suppression. Leveraging this axis represents a new strategy for the management of GBM that may synergize with standard of care chemo-, radio-, and immunotherapies.

摘要：胶质母细胞瘤（GBM）是成人最常见的恶性原发性脑肿瘤。 GBM生长 和治疗耐药性是由自我更新的癌症干细胞（CSC）和衰老细胞共同驱动的 诱导肿瘤支持微环境。 CSC 受细胞内在遗传和表观遗传调节 网络、细胞与周围微环境的外在相互作用以及细胞之间的相互作用 这些内在和外在的监管计划。虽然驱动自我更新的多种分子机制 已经确定，高龄对 CSC 维持的影响仍有待探索。具体来说，就是 目前尚不清楚高龄如何改变 CSC 维持和 GBM 生长。最近公认的一个标志 高龄是含硫氨基酸代谢的转变，抑制酶依赖性硫化氢 (H2S) 的产生、信号传导和生物利用度。 H2S 是一种氧化还原活性代谢物，通过蛋白质 S- 发出信号 硫化作用 (R-SSnH) 并影响新陈代谢、免疫激活和寿命。其酶法生产 胱硫醚 γ-裂解酶 (CGL) 受到甲状腺激素 (TH) 的抑制。 H2S 具有促肿瘤和抗肿瘤作用 功能依赖于肿瘤类型。然而，关于细胞内在和肿瘤的信息有限。 GBM 中 H2S 的微环境功能。最近，我们通过饮食和调节 H2S 水平 药物干预，发现 H2S 在 GBM 中起到肿瘤抑制作用并减弱 CSC 临床前模型中的自我更新和肿瘤生长。人体中 H2S 的生成和硫化作用减少 GBM 标本与非肿瘤对照相比。虽然数据支持 H2S 起作用的假设 作为 GBM 中的肿瘤抑制因子，衰老引起的 H2S 对 GBM 进展和 CSC 的影响下降，并且 如何扭转这种情况以用于临床，尚未探索。根据我们发表的调查结果和新的初步数据， 我们假设衰老过程中 H2S 产生的减少会促进 CSC 的启动、免疫 抑制，并推动 GBM 生长，但最终可以通过基于抗 TH 的 H2S 增强来逆转 接近。我们将通过整合我们新开发的 H2S 和 与操纵 H2S 的体外和体内 GBM 模型相结合的硫化检测分析 通过对人类样本进行遗传和药理学干预来生产，以提供临床相关性。目的 图 1 检验了以下假设：衰老诱导的 CGL 衍生 H2S 抑制会加速 GBM 进展。目的 2 检验化学诱导的甲状腺功能减退症刺激 CGL 增加全身和神经的假设 H2S 产生可减少 GBM 进展、CSC 富集并提高临床前生存率 GBM 模型。该项目的长期目标是探究 H2S 作为 GBM 肿瘤抑制因子的功能 衰老过程中丢失的能量，同时还研究甲状腺功能减退引起的 H2S 产生的治疗效果和 信号传导以减少 CSC 维持和免疫抑制。利用这个轴代表了一种新的策略 用于 GBM 的管理，可与标准护理化疗、放疗和免疫疗法协同作用。