Glutaredoxin, Glutathione Metabolism and Lung Cancer
谷氧还蛋白、谷胱甘肽代谢与肺癌
基本信息
- 批准号:10657945
- 负责人:
- 金额:$ 53.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-10 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdenovirusesAmino AcidsAntioxidantsAttenuatedBindingBiochemistryBreedingCessation of lifeCisplatinClinicalCysteineCystineDependovirusDevelopmentEnterobacteria phage P1 Cre recombinaseEnvironmentGlutamatesGlutathioneGlutathione Metabolism PathwayGrowthHomeostasisHumanImmune checkpoint inhibitorIn VitroKRAS2 geneKRASG12DLinkLung AdenocarcinomaLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetabolismMusNADPOncogenicOrganoidsOxidantsOxidation-ReductionOxidative StressPathogenesisPathway interactionsPharmaceutical PreparationsPharmacologic SubstancePropertyProtein SProteinsProteomicsRefractoryRegimenResistanceRoleSignal TransductionStructureSulfhydryl CompoundsSystemTestingTherapeuticTimeTissuesTreatment EfficacyTumor BurdenUbiquitinationXenograft procedureantiportercombatglutaredoxinglutaredoxin 2human subjectinsightlung cancer celllung tumorigenesismutantneoplastic cellnovel therapeutic interventionovarian neoplasmpenicillamine-glutathione mixed disulfidepreclinical developmentpreventside effectstandard of caretumortumor growthtumorigenesistumorigenicubiquitin isopeptidase
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.
项目摘要
谷胱甘肽(GSH)是一种小的巯基抗氧化剂,在维持氧化还原稳态中至关重要,并增加
谷胱甘肽在KRAS突变型肺腺癌中存在。谷胱甘肽也可导致S-谷胱甘肽化
(PSSG),GSH与蛋白质中的反应性半胱氨酸的缀合,其可以通过脱-
谷胱甘肽酶,谷氧还蛋白(GLRX)。虽然谷氧还蛋白/PSSG系统已经成为一个关键的调节因子,
氧化还原信号,很少有人知道它在肺腺癌(LUAD)的中断。我们创造了令人兴奋的
发现GLRX表达在人LUAD中降低,并且KrasG 12 D诱导的肺肿瘤发生是
在缺乏Glycogen的小鼠中增强。在氧化还原蛋白质组学筛选中,我们发现,
卵巢肿瘤去泛素化酶OTUB 1,最近被鉴定为XC-系统的调节剂。系统XC-是
一种胱氨酸/谷氨酸反向转运蛋白,输出谷氨酸并输入胱氨酸,胱氨酸反过来在细胞内被还原
半胱氨酸,谷胱甘肽合成中的限速氨基酸。系统XC-由SLC 7A 11和
SLC3A2。OTUB 1与SLC 7A 11结合以防止其泛素化和蛋白酶体降解。我们取得了
令人兴奋的发现是OTUB 1的S-谷胱甘肽化在SLC 7A 11的稳定中是重要的,导致
GSH的增加。与邻近的对照组织相比,OTUB 1和SLC 7A 11的表达增加,
LUAD。这些令人兴奋的发现使我们假设,谷氧还蛋白表达的减少,
KRAS驱动的肺腺癌通过S-
卵巢肿瘤去泛素化酶1(OTUB 1)的谷胱甘肽化,增加谷胱甘肽并促进
肺癌细胞的存活。此外,我们假设增加谷氧还蛋白的途径将减少,
GSH水平导致顺铂诱导的肺癌细胞杀伤效力增加。具体目标1,
将确定GLRX状态是否控制KrasG 12 D诱导的肿瘤发生。具体目标2建议,
解决OTUB 1 S-谷胱甘肽化和系统XC-在KrasG 12 D中增加GSH的重要性-
而在具体目标3中,我们旨在解决AAV介导的GLRX转导对肿瘤的影响。
顺铂诱导的小鼠原发性LUAD肿瘤类器官和KrasG 12 D驱动的肿瘤中的肿瘤杀伤。完成
这一建议将提供新的见解GLRX-蛋白S-谷胱甘肽氧化还原系统的作用,
LUAD的发病机制,并提供了一个理由,增加GLRX在肺肿瘤,以促进杀伤。
GLRX的药物开发有可能提供新的治疗策略来对抗LUAD,
与标准护理疗法相结合。
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:
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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