线粒体活性氧通过气真皮蛋白D促进肿瘤转移和肿瘤微环境免疫抑制。

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Naijun Miao, Zhengchun Kang, Zhuning Wang, Wenyan Yu, Ting Liu, Ling-Zhijie Kong, Ying Zheng, Changli Ding, Zhiyong Zhang, Chen Zhong, Qingliang Fang, Kaichun Li
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引用次数: 0

摘要

虽然最近的研究已经证实,驱动焦亡的气皮蛋白D (GSDMD)对细胞死亡和炎症至关重要,但其在癌症转移中的作用尚未阐明。在本研究中,GSDMD在小鼠正异性4T1乳腺癌模型转移期肺中性粒细胞中显著升高。此外,劈裂型GSDMD的N端结构域与线粒体活性氧(mROS)和血清高迁移率组盒1 (HMGB-1)水平升高呈正相关。从机制上讲,抑制mROS可显著抑制GSDMD-N寡聚和孔隙形成。此外,在组织蛋白酶c治疗后,GSDMD的激活显著增强了中性粒细胞胞外陷阱(NETs)的形成。在使用4T1细胞系的小鼠原位乳腺癌模型中,通过应用LDC7559抑制GSDMD显著减弱了乳腺癌向肺部的转移扩散。此外,敲除GSDMD可减少E0771静脉注射小鼠模型的肺转移。此外,抑制GSDMD可减少乳腺癌小鼠模型转移性肺中髓系衍生抑制细胞(myeloid derived suppressor cells, MDSC)的数量,同时增加CD8+ T细胞的百分比和总细胞计数,提示线粒体功能障碍依赖的GSDMD激活可促进肿瘤微环境免疫抑制和NETs。GSDMD是缓解乳腺癌向肺转移进展的一个有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondrial reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D.

Although recent research has established that gasdermin D (GSDMD), a factor that drives pyroptosis, is essential for cell death and inflammation, its involvement in cancer metastasis has yet to be elucidated. In this study, GSDMD was significantly increased in lung neutrophils at the metastatic stage from a murine orthotropic 4T1 breast cancer model. Moreover, the N terminal domain from cleaved GSDMD exhibited a positive correlation with increased mitochondrial reactive oxygen species (mROS) and serum high mobility group box 1 (HMGB-1) levels. Mechanistically, mROS inhibition significantly suppressed GSDMD-N oligomerization and pore formation. In addition, the activation of GSDMD significantly enhanced the formation of neutrophil extracellular traps (NETs) following treatment with Cathepsin C. Within a murine orthotopic breast cancer model using 4T1 cell line, the inhibition of GSDMD through the application of LDC7559 significantly attenuated the metastatic spread of breast cancer to the lung. In addition, knockout of GSDMD reduced lung metastasis in E0771 intravenous injection murine model. Furthermore, inhibition of GSDMD reduced the number of myeloid derived suppressor cells (MDSC) in the metastatic lung of breast cancer mouse model, while concurrently increasing both the percentage and total cell count of CD8+ T cells, suggesting that mitochondrial dysfunction-dependent GSDMD activation promotes tumor microenvironment immunosuppression and NETs. GSDMD represents a promising therapeutic target for mitigating the metastatic progression of breast cancer to the lung.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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