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: 10818004
• 负责人: Isaac Spencer Harris
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818004
• 关键词: Ablation; Amino Acids; Antioxidants; Cancer Intervention; Catabolism; Cysteine; Cystine; Data; Dipeptides; Gamma-glutamyl transferase; Glutathione; Glycine; Goals; Growth; Malignant Neoplasms; Mammary Neoplasms; Mediating; Plasma Cells; Research; Source; Supplementation; Testing; Therapeutic; Tissues; Tumor Promotion; Work; cancer cell; cancer subtypes; cancer therapy; cell growth; cysteinylglycine; experimental study; extracellular; in vivo; interest; novel; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; 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 人们对阻断抗氧化剂用于癌症治疗产生了新的兴趣，但抗氧化剂如何促进癌症生长尚不清楚 不清楚。谷胱甘肽 (GSH) 是体内最丰富的抗氧化剂，我们之前的工作表明 GSH 促进三阴性乳腺癌 (TNBC) 的肿瘤发生。一般认为 GSH 的作用 在细胞内作为癌细胞的抗氧化剂。然而，我们的初步研究表明，阻断细胞内 GSH 合成不会阻碍 TNBC 生长。这些令人惊讶的结果表明了一种替代机制 其中细胞外谷胱甘肽支持乳腺肿瘤的生长。该提案的总体目标是确定 细胞外谷胱甘肽如何促进肿瘤生长。众所周知，细胞外谷胱甘肽存在于血浆中，但细胞 无法导入 GSH。相反，GSH 通过 γ-谷氨酰转移酶 (GGT1) 代谢产生谷氨酰- 二肽和半胱氨酰甘氨酸，产生胱氨酸和甘氨酸。事实上，我们发现 GSH 合成的消除 体内不仅降低循环中的谷胱甘肽，而且还降低体内半胱氨酰甘氨酸、半胱氨酸和甘氨酸的水平。 组织。此外，我们表明补充 GSH 和半胱氨酰甘氨酸可以挽救 TNBC 生长 胱氨酸消耗分别以 GGT1 依赖性和非依赖性方式进行。综合起来，这些初步数据 提出了一种替代机制，其中 GSH 作为代谢物的循环来源而不是作为 直接抗氧化剂。在这个提案中，我们描述了将检验以下假设的实验： 肿瘤 GGT1 的细胞外 GSH 支持 TNBC 生长。在目标 1 中，我们将阐明细胞外的影响 GSH 对 TNBC 增长的影响。在目标 2 中，我们确定了 TNBC 对 GGT1 介导的 GSH 分解代谢的依赖。瞄准 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组全新的 TNBC 未实现的目标和治疗策略。