ArticleCell communication and signaling : CCS2025
ACACA depletion activates the cPLA2-arachidonic acid-NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Nuciferine Suppresses Inflammatory Hepatocarcinogenesis by Targeting cPLA2-Dependent Arachidonic Acid Metabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Alisol A 23,24-diacetate improves LPS-induced acute lung injury through the IL-17A/NF-κB signaling pathway.Chinese medicine · 2026Article
- Ugonin J Inhibits EMT and Migration in Prostate Cancer by Suppressing ADAM9 Expression.Oncology research · 2026Article
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15 authors.
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Abstract
backgroundAcetyl-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.
methodsACACA 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.
resultsACACA 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.
conclusionsThis 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.
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