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: 10746501
• 负责人: Isaac Spencer Harris
• 金额: $ 5.99万
• 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/10746501
• 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)是一种侵袭性的癌症亚型，治疗选择有限。的确有 阻止抗氧化剂用于癌症治疗是一个新的兴趣，但抗氧化剂如何促进癌症生长是 不清楚。谷胱甘肽(GSH)是人体内含量最丰富的抗氧化剂，我们之前的研究表明 GSH促进三阴性乳腺癌(TNBC)的发生。一般认为谷胱甘肽起作用 作为癌细胞内的抗氧化剂。然而，我们的初步研究表明，阻断细胞内 GSH合成不会阻碍TNBC的生长。这些令人惊讶的结果表明了另一种机制 细胞外GSH支持乳腺肿瘤的生长。这项提案的首要目标是确定 细胞外GSH如何促进肿瘤生长。已知细胞外GSH存在于血浆和细胞中 无法导入GSH。相反，谷胱甘肽由谷氨酰转移酶(GGT1)代谢产生谷氨酰基转移酶(GGT1)。 二肽和半胱氨酸甘氨酸，产生半胱氨酸和甘氨酸。事实上，我们发现消融GSH合成 在体内，不仅降低循环中的GSH，而且还降低半胱氨酸甘氨酸、半胱氨酸和甘氨酸的水平 纸巾。此外，我们还发现补充谷胱甘肽和半胱氨酸甘氨酸可以挽救TNBC的生长。 半胱氨酸的耗竭分别以GGT1依赖和非依赖的方式进行。总而言之，这些初步数据 提出一种替代机制，使谷胱甘肽作为代谢物的循环来源而不是 直接抗氧化剂。在这个提议中，我们描述了一些实验，这些实验将检验这样一个假设，即人体的分解代谢 肿瘤GGT1分泌的细胞外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生长的影响。在目标2中，我们确定了TNBC对GGT1介导的GSH分解代谢的依赖。在AIM 3，我们将确定半胱氨酸甘氨酸为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出一套全新的 未实现的TNBC的目标和治疗策略。