Hydrogen sulfide functions as a tumor suppressor in glioblastoma

摘要：胶质母细胞瘤(GBM)是成人最常见的原发恶性脑肿瘤。GBM增长 而治疗耐药性是由自我更新的癌症干细胞(CSCs)和衰老共同驱动的。 诱导肿瘤支持微环境。CSCs受细胞内在遗传和表观遗传调控 网络，与周围微环境的外在细胞相互作用，以及相互作用 那些内在和外在的监管计划。而驱动自我更新的多种分子机制 尽管已经确定，高龄对CSC维持的影响仍有待探讨。具体地说，它是 不清楚高龄如何改变CSC的维护和GBM的增长。最近公认的一个标志 高龄是含硫氨基酸代谢的转变，它抑制了依赖酶的硫化氢 (硫化氢)产生、信号传递和生物利用度。硫化氢是一种氧化还原活性代谢产物，通过蛋白质S传递信号- 硫酸盐水合作用(R-SSnH)并影响新陈代谢、免疫激活和寿命。它的酶促生产 胱硫醚γ裂解酶受甲状腺激素(TH)的抑制。硫化氢具有促肿瘤和抗肿瘤双重作用 与肿瘤类型相关的功能。然而，关于细胞内源性和肿瘤的信息有限。 硫化氢在GBM中的微环境作用。最近，我们通过饮食和营养调节硫化氢水平。 药物干预，发现硫化氢在GBM中作为肿瘤抑制因子发挥作用，并减弱CSC 临床前模型中的自我更新和肿瘤生长。人的硫化氢生成和硫水化作用减少 基底膜标本与非肿瘤对照比较。虽然数据支持硫化氢起作用的假设 作为GBM中的肿瘤抑制因子，衰老诱导的硫化氢对GBM进展和CSCs的影响减弱，并且 如何将其逆转用于临床，尚不清楚。根据我们公布的发现和新的初步数据， 我们假设在衰老过程中减少硫化氢的产生促进了CSC的启动、免疫 抑制，并推动GBM增长，但最终可以通过基于TH的反H2S助推而逆转 接近了。我们将通过将我们最新开发的硫化氢和 结合体外和体内操纵硫化氢的GBM模型的硫水化检测方法 通过对人类样本进行遗传和药理学干预来产生，以提供临床相关性。目标 1检验了这样的假设，即衰老诱导的CGL衍生的硫化氢抑制加速了GBM的进展。目标 2验证了化学诱导的甲状腺功能减退症刺激CGL增加全身和神经功能的假设 硫化氢的产生导致GBM进展减少，CSC浓缩，并提高临床前患者的存活率 GBM模型。这个项目的长期目标是询问硫化氢作为一种GBM肿瘤抑制因子的功能 在研究甲状腺功能减退诱导的硫化氢产生和治疗效果的同时，衰老过程中这些物质也会消失。 信号传递以减少CSC的维护和免疫抑制。利用这一轴心代表着一种新的战略 对于GBM的管理，可能与标准的化疗、放射和免疫疗法协同作用。

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.