Downregulation of ATP5F1D inhibits mtROS/NLRP3/caspase-1/GSDMD axis to suppress pyroptosis-mediated malignant progression of endometrial cancer.

IF 4.8 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2024-09-30 Epub Date: 2024-07-28 DOI:10.1016/j.intimp.2024.112808

Yuemei Cheng, Xi Chen, Dan Hu, Junhong Du, Yijuan Xing, Xiaolei Liang, Yongxiu Yang

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Abstract

Purpose: In developed countries, endometrial cancer (EC) is the most prevalent gynecological cancer and its occurrence is associated with chronic inflammation. ATP5F1D is a subunit of ATP synthase (complex V), as well as the important component of mitochondrial electron transport chain (ETC). ETC play compelling roles in carcinogenesis. To date, little is known about the role of ATP5F1D in EC.

Methods: ATP5F1D expression was identified in EC tissues and EC cell lines. We evaluated the influence of ATP5F1D on clinical features and prognosis based on TCGA database. The effects of ATP5F1D in EC malignant progression by applying loss-of-function assays in KLE and Ishikawa cell lines were detected by EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Additionally, electron microscope, LDH release, ELISA, mitochondrial ROS measurement, and Immunofluorescence were performed to demonstrate ATP5F1D can affect the pyroptosis of EC. To observe the anti-tumor effect on ATP5F1D silencing, we established an in vivo human endometrial tumor model using nude mice.

Results: ATP5F1D expression was significantly upregulated in EC and was associated with favorable prognosis. ATP5F1D knockdown inhibited the proliferation, invasion, and migration of EC cells. Similarly, in nude mice, ATP5F1D knockdown suppressed the growth EC cells. Knocking down ATP5F1D lead to decrease the production of mitochondrial ROS (mtROS) and inhibited pyroptosis of EC cells.

Conclusion: Downregulation of ATP5F1D as a new therapeutic strategy that could mediate pyroptosis via suppressing mtROS/NLRP3/caspase-1/GSDMD pathway to inhibit EC progression.

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下调ATP5F1D可抑制mtROS/NLRP3/caspase-1/GSDMD轴，从而抑制子宫内膜癌热毒症介导的恶性进展。

目的：在发达国家，子宫内膜癌（EC）是发病率最高的妇科癌症，其发生与慢性炎症有关。ATP5F1D 是 ATP 合成酶（复合物 V）的一个亚基，也是线粒体电子传递链（ETC）的重要组成部分。ETC 在致癌过程中发挥着重要作用。迄今为止，人们对 ATP5F1D 在欧共体中的作用知之甚少：方法：在心肌组织和心肌细胞系中发现了 ATP5F1D 的表达。我们基于 TCGA 数据库评估了 ATP5F1D 对临床特征和预后的影响。在 KLE 和 Ishikawa 细胞系中应用功能缺失试验，通过 EdU、CCK-8、伤口愈合、Transwell 和流式细胞术检测 ATP5F1D 对 EC 恶性进展的影响。此外，还通过电子显微镜、LDH 释放、ELISA、线粒体 ROS 测量和免疫荧光来证明 ATP5F1D 能影响 EC 的热休克。为了观察沉默 ATP5F1D 的抗肿瘤作用，我们利用裸鼠建立了体内人子宫内膜肿瘤模型：结果：ATP5F1D在EC中表达明显上调，并与良好的预后相关。结果：ATP5F1D在EC中表达明显上调，并与预后良好相关。ATP5F1D敲除可抑制EC细胞的增殖、侵袭和迁移。同样，在裸鼠体内，ATP5F1D 基因敲除抑制了癌细胞的生长。敲除 ATP5F1D 可减少线粒体 ROS（mtROS）的产生，抑制 EC 细胞的热凋亡：结论：下调ATP5F1D是一种新的治疗策略，它可以通过抑制mtROS/NLRP3/caspase-1/GSDMD通路介导热凋亡，从而抑制EC的发展。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.