Impact of extracellular glutathione catabolism on triple-negative breast cancer

细胞外谷胱甘肽分解代谢对三阴性乳腺癌的影响

• 批准号: 10418563
• 负责人: Isaac Spencer Harris
• 金额: $ 38.82万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-18 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418563
• 关键词: Ablation; Affect; Amino Acids; Antioxidants; Breast Cancer Cell; Cancer Intervention; Catabolism; Cells; Cellular Metabolic Process; Cysteine; Cystine; Data; Dipeptidases; Dipeptides; GTP-Binding Protein alpha Subunits, Gs; Gamma-glutamyl transferase; Gatekeeping; Genetic; Glutamates; Glutathione; Glycine; Goals; Growth; In Vitro; Intercellular Fluid; Malignant Neoplasms; Mammary Neoplasms; Mediating; Outcome; Perception; Plasma; Plasma Cells; Proteins; Research; Role; Source; Supplementation; Testing; Tissues; Work; antioxidant therapy; breast tumorigenesis; cancer cell; cancer subtypes; cancer therapy; cysteinylglycine; deprivation; experimental study; extracellular; in vivo; interest; malignant breast neoplasm; mouse model; new therapeutic target; novel; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. There is an emerging interest in blocking antioxidants for cancer therapy, but how antioxidants promote cancer growth is unclear. Glutathione (GSH) is the most abundant antioxidant in the body and our previous work has shown that GSH promotes tumorigenesis of triple-negative breast cancers (TNBC). It is generally assumed that GSH acts intracellularly as an antioxidant in cancer cells. However, our preliminary studies show that blocking intracellular GSH synthesis does not impede TNBC growth. These surprising results suggest an alternative mechanism where extracellular GSH supports breast tumor growth. The overarching goal of this proposal is to determine how extracellular GSH promotes tumor growth. It is known that extracellular GSH is present in plasma but cells cannot import GSH. Instead, GSH is metabolized by gamma-glutamyl transferase (GGT1) to produce a glutamyl- dipeptide and cysteinylglycine, which yields cystine and glycine. Indeed, we find that ablation of GSH synthesis in vivo not only lowers circulating GSH but also reduces the levels of cysteinylglycine, cysteine, and glycine in tissues. Further, we show that supplementation with GSH and cysteinylglycine can rescue TNBC growth upon cystine depletion in GGT1-dependent and -independent manners, respectively. Together, these preliminary data suggest an alternative mechanism where GSH functions as a circulating source of metabolites rather than as a direct antioxidant. In this proposal, we describe experiments that will test the hypothesis that the catabolism of extracellular GSH by tumor GGT1 supports TNBC growth. In Aim 1, we will elucidate the impact of extracellular GSH on TNBC growth. In Aim 2, we identify the reliance of TNBC on GGT1-mediated GSH catabolism. In Aim 3, we will determine the mechanisms by which cysteinylglycine supplies cysteine for TNBC growth. Our research will challenge the paradigm of antioxidant function in cancer by describing a novel mechanism of GSH function as a circulating source of amino acids. Further, these studies have the potential to reveal a completely new set of unrealized targets and therapeutic strategies for TNBC.

三阴性乳腺癌（TNBC）是一种侵袭性癌症亚型，治疗选择有限。有 阻断抗氧化剂用于癌症治疗的新兴趣，但抗氧化剂如何促进癌症生长， 不清楚谷胱甘肽（GSH）是体内最丰富的抗氧化剂，我们以前的工作表明， GSH促进三阴性乳腺癌（TNBC）的肿瘤发生。一般认为GSH的作用 在癌细胞内作为抗氧化剂。然而，我们的初步研究表明， GSH合成不阻碍TNBC生长。这些令人惊讶的结果表明了另一种机制 其中细胞外GSH支持乳腺肿瘤生长。本提案的总体目标是确定 细胞外GSH如何促进肿瘤生长。已知细胞外GSH存在于血浆中，而细胞内 不能输入GSH。相反，GSH通过γ-谷氨酰转移酶（GGT 1）代谢，产生谷氨酰-谷氨酰-谷胱甘肽。 二肽和半胱氨酰甘氨酸，其产生胱氨酸和甘氨酸。事实上，我们发现， 在体内不仅降低了循环GSH，而且降低了半胱氨酰甘氨酸、半胱氨酸和甘氨酸的水平， 组织中此外，我们表明，补充GSH和半胱氨酰甘氨酸可以挽救TNBC生长， 分别以GGT 1依赖性和非依赖性方式消耗胱氨酸。这些初步数据 这表明GSH作为代谢物循环来源而不是作为代谢物循环来源的替代机制。 直接抗氧化剂在这个建议中，我们描述了实验，将测试的假设， 通过肿瘤GGT 1的细胞外GSH支持TNBC生长。在目标1中，我们将阐明细胞外 GSH对TNBC生长的影响。在目的2中，我们确定了TNBC对GGT 1介导的GSH催化剂的依赖性。在Aim中 3，我们将确定半胱氨酰甘氨酸为TNBC生长提供半胱氨酸的机制。我们的研究 将通过描述GSH功能的新机制来挑战癌症中抗氧化功能的范式 作为氨基酸的循环来源。此外，这些研究有可能揭示一套全新的 未实现的目标和TNBC的治疗策略。