Glutaredoxin, Glutathione Metabolism and Lung Cancer

谷氧还蛋白、谷胱甘肽代谢与肺癌

基本信息

项目摘要

PROJECT SUMMARY Glutathione (GSH) is a small thiol antioxidant that is critical in maintaining redox homeostasis, and increases in glutathione occur in KRAS-mutant lung adenocarcinoma. Glutathione can also lead to S-glutathionylation (PSSG), the conjugation of GSH to reactive cysteines in proteins, which can be reversed by the de- glutathionylase, glutaredoxin (GLRX). While the glutaredoxin/PSSG system has emerged as a key regulator of redox signaling, little is known about its disruption in lung adenocarcinoma (LUAD). We have made the exciting discovery that GLRX expression is decreased in human LUAD and that KrasG12D-induced lung tumorigenesis is enhanced in mice lacking Glrx. In a redox proteomics screen we revealed increases in S-glutathionylation of ovarian tumor deubiquitinase, OTUB1, which was recently identified as a regulator of System XC-. System XC- is a cystine/glutamate antiporter that exports glutamate and imports cystine, which is in turn reduced intracellularly to cysteine, the rate limiting amino acid in glutathione synthesis. System XC- is composed of SLC7A11 and SLC3A2. OTUB1 binds to SLC7A11 to prevent its ubiquitination and proteasomal degradation. We have made the exciting discovery that S-glutathionylation of OTUB1 is important in the stabilization of SLC7A11, leading to increases in GSH. Compared to adjacent control tissue, expression of OTUB1 and SLC7A11 are increased in LUAD. These exciting findings led us to hypothesize that decreases in glutaredoxin expression in mutant KRAS-driven lung adenocarcinoma cause increases in system XC- activity through the S- glutathionylation of ovarian tumor deubiquitinase 1 (OTUB1), augmenting glutathione and promoting survival of lung cancer cells. Furthermore, we hypothesize that avenues to augment glutaredoxin will diminish GSH levels leading to increased potency of cisplatin-induced killing of lung cancer cells. In Specific Aim 1 we will determine whether GLRX status controls KrasG12D-induced tumorigenesis. Specific Aim 2 proposes to address the importance of OTUB1 S-glutathionylation and System XC- in the augmentation of GSH in KrasG12D- induced tumors while in Specific Aim 3 we aim to address the impact of AAV-mediated transduction of GLRX on cisplatin-induced tumor killing in primary LUAD tumor organoids and KrasG12D-driven tumors in mice. Completion of this proposal will provide new insights into the role of the GLRX-protein S-glutathionylation redox system in the pathogenesis of LUAD and offers a rationale for augmenting GLRX in lung tumors in order to promote killing. The pharmaceutical development of GLRX has the potential to offer new therapeutic strategies to combat LUAD, in combination with standard of care therapy.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Yvonne M. W. Janssen-Heininger其他文献

Small molecule-mediated inhibition of the oxidoreductase ERO1A restrains aggressive breast cancer by impairing VEGF and PD-L1 in the tumor microenvironment
小分子介导的氧化还原酶 ERO1A 的抑制通过损害肿瘤微环境中的血管内皮生长因子和程序性死亡配体 1 来抑制侵袭性乳腺癌
  • DOI:
    10.1038/s41419-025-07426-1
  • 发表时间:
    2025-02-17
  • 期刊:
  • 影响因子:
    9.600
  • 作者:
    Ersilia Varone;Michele Retini;Alessandro Cherubini;Alexander Chernorudskiy;Alice Marrazza;Andrea Guidarelli;Alfredo Cagnotto;Marten Beeg;Marco Gobbi;Stefano Fumagalli;Marco Bolis;Luca Guarrera;Maria Chiara Barbera;Chiara Grasselli;Augusto Bleve;Daniele Generali;Manuela Milani;Michele Mari;Mario Salmona;Giovanni Piersanti;Giovanni Bottegoni;Massimo Broggini;Yvonne M. W. Janssen-Heininger;Jaehyung Cho;Orazio Cantoni;Ester Zito
  • 通讯作者:
    Ester Zito

Yvonne M. W. Janssen-Heininger的其他文献

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{{ truncateString('Yvonne M. W. Janssen-Heininger', 18)}}的其他基金

Collagen Oxidation, Myofibroblast Activation and Age-Associated Pulmonary Fibrosis
胶原蛋白氧化、肌成纤维细胞激活和年龄相关性肺纤维化
  • 批准号:
    10532853
  • 财政年份:
    2022
  • 资助金额:
    $ 53.51万
  • 项目类别:
Collagen Oxidation, Myofibroblast Activation and Age-Associated Pulmonary Fibrosis
胶原蛋白氧化、肌成纤维细胞激活和年龄相关性肺纤维化
  • 批准号:
    10445737
  • 财政年份:
    2021
  • 资助金额:
    $ 53.51万
  • 项目类别:
2020 Oxygen Radicals Gordon Research Conference (GRC) and Gordon Research Seminar (GRS)
2020年氧自由基戈登研究会议(GRC)和戈登研究研讨会(GRS)
  • 批准号:
    9912443
  • 财政年份:
    2020
  • 资助金额:
    $ 53.51万
  • 项目类别:
S-glutathionylation chemistry in fibrotic lung remodeling
纤维化肺重塑中的 S-谷胱甘肽化学
  • 批准号:
    10585922
  • 财政年份:
    2017
  • 资助金额:
    $ 53.51万
  • 项目类别:
S-glutathionylation chemistry in fibrotic lung remodeling
纤维化肺重塑中的 S-谷胱甘肽化学
  • 批准号:
    10320789
  • 财政年份:
    2017
  • 资助金额:
    $ 53.51万
  • 项目类别:
Redox-based Fas signaling in allergic airway disease
过敏性气道疾病中基于氧化还原的 Fas 信号传导
  • 批准号:
    7822474
  • 财政年份:
    2009
  • 资助金额:
    $ 53.51万
  • 项目类别:
Epithelial JNK-TGFb1 Signaling Axis in Airway Remodeling
气道重塑中的上皮 JNK-TGFb1 信号轴
  • 批准号:
    7367482
  • 财政年份:
    2008
  • 资助金额:
    $ 53.51万
  • 项目类别:
Epithelial JNK-TGFb1 Signaling Axis in Airway Remodeling
气道重塑中的上皮 JNK-TGFb1 信号轴
  • 批准号:
    7644952
  • 财政年份:
    2008
  • 资助金额:
    $ 53.51万
  • 项目类别:
Redox Biology in COPD
慢性阻塞性肺病中的氧化还原生物学
  • 批准号:
    7690866
  • 财政年份:
    2008
  • 资助金额:
    $ 53.51万
  • 项目类别:
Epithelial JNK-TGFb1 Signaling Axis in Airway Remodeling
气道重塑中的上皮 JNK-TGFb1 信号轴
  • 批准号:
    8459777
  • 财政年份:
    2008
  • 资助金额:
    $ 53.51万
  • 项目类别:

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