ACACA缺失激活cpla2 -花生四烯酸- nf -κB轴,驱动雄激素受体非依赖性前列腺癌的炎症重编程。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Yongding Wu, Huijing Tan, Hongwei Luo, Huichan He, Jiarun Lai, Weide Zhong
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In ARIPC cell lines, ACACA was inhibited via both shRNA and the pharmacological inhibitor TOFA. Transcriptomic, metabolomic, and single-cell RNA sequencing data were used to identify downstream changes. Inflammatory signaling was assessed by qPCR, western blotting, and immunofluorescence. Cell migration was evaluated via wound healing and transwell assays, and the metastatic potential was examined in a mouse tail vein injection model. The roles of arachidonic acid (AA), cytosolic phospholipase A2 (cPLA2), and NF-κB signaling were further tested through targeted inhibition.</p><p><strong>Results: </strong>ACACA expression was reduced in ARIPC and was negatively correlated with inflammatory pathways. Its inhibition upregulated proinflammatory cytokines and chemokines, elevated AA and eicosanoid levels, and increased cPLA2 expression. Single-cell RNA sequencing confirmed NF-κB signaling enrichment in ACACA-low tumor cells. Mechanistically, elevated AA activated NF-κB signaling. 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引用次数: 0

摘要

背景:乙酰辅酶a羧化酶(ACACA)是脂肪酸生物合成的关键酶,是前列腺癌的治疗靶点。然而,它在雄激素受体非依赖性前列腺癌(ARIPC)中的作用尚不清楚,ARIPC是一种侵袭性和治疗耐药亚型。本研究旨在探讨ACACA缺失对ARIPC的影响,重点关注炎症和转移。方法:对多个转移性去势抵抗性前列腺癌(mCRPC)数据集的ACACA表达模式进行分析。在ARIPC细胞系中,ACACA可通过shRNA和药理抑制剂TOFA抑制。转录组学、代谢组学和单细胞RNA测序数据用于鉴定下游变化。通过qPCR、western blotting和免疫荧光检测炎症信号。通过伤口愈合和transwell实验评估细胞迁移,并在小鼠尾静脉注射模型中检测转移潜力。通过靶向抑制进一步检测花生四烯酸(AA)、胞质磷脂酶A2 (cPLA2)和NF-κB信号通路的作用。结果:ACACA在ARIPC中表达降低,与炎症通路呈负相关。它的抑制上调了促炎细胞因子和趋化因子,升高了AA和类二十烷水平,增加了cPLA2的表达。单细胞RNA测序证实在低acaca肿瘤细胞中NF-κB信号富集。机制上,AA升高激活了NF-κB信号。ACACA缺失增强了细胞迁移和转移以及巨噬细胞的浸润。抑制cPLA2或NF-κB信号可以逆转这些作用。结论:本研究揭示了一种以前未被认识到的ARIPC中ACACA缺失的促肿瘤作用。在这种情况下,通过花生四烯酸介导的NF-κB信号激活,靶向ACACA可增强炎症和转移。这些发现强调了ACACA抑制的环境依赖性,肿瘤促进作用,并强调了在代谢治疗中需要联合策略来避免潜在的不良后果。试验注册:不适用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ACACA depletion activates the cPLA2-arachidonic acid-NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer.

Background: Acetyl-CoA carboxylase alpha (ACACA) is a key enzyme in fatty acid biosynthesis and a proposed therapeutic target in prostate cancer. However, its role in androgen receptor-independent prostate cancer (ARIPC), an aggressive and treatment-resistant subtype, remains unclear. This study aimed to investigate the effects of ACACA depletion on ARIPC, with a focus on inflammation and metastasis.

Methods: ACACA expression patterns were analyzed across multiple metastatic castration-resistant prostate cancer (mCRPC) datasets. In ARIPC cell lines, ACACA was inhibited via both shRNA and the pharmacological inhibitor TOFA. Transcriptomic, metabolomic, and single-cell RNA sequencing data were used to identify downstream changes. Inflammatory signaling was assessed by qPCR, western blotting, and immunofluorescence. Cell migration was evaluated via wound healing and transwell assays, and the metastatic potential was examined in a mouse tail vein injection model. The roles of arachidonic acid (AA), cytosolic phospholipase A2 (cPLA2), and NF-κB signaling were further tested through targeted inhibition.

Results: ACACA expression was reduced in ARIPC and was negatively correlated with inflammatory pathways. Its inhibition upregulated proinflammatory cytokines and chemokines, elevated AA and eicosanoid levels, and increased cPLA2 expression. Single-cell RNA sequencing confirmed NF-κB signaling enrichment in ACACA-low tumor cells. Mechanistically, elevated AA activated NF-κB signaling. ACACA depletion enhanced cell migration and metastasis, along with macrophage infiltration. Inhibiting cPLA2 or NF-κB signaling reversed these effects.

Conclusions: This study reveals a previously unrecognized tumor-promoting effect of ACACA depletion in ARIPC. Targeting ACACA in this context enhances inflammation and metastasis via arachidonic acid-mediated activation of NF-κB signaling. These findings highlight a context dependent, tumor-promoting role of ACACA inhibition and underscore the need for combinational strategies to avoid potential adverse outcomes in metabolic therapies.

Trial registration: Not applicable.

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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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