AK4 promotes nasopharyngeal carcinoma metastasis and chemoresistance by activating NLRP3 inflammatory complex

Cell Death Dis. 2025 Jul 1;16(1):480. doi: 10.1038/s41419-025-07805-8.

Abstract

Metastasis is the main cause of treatment failure in nasopharyngeal carcinoma (NPC). Our previous study developed a transcriptomics-based gene signature (AK4, CPAMD8, DDAH1, and CRTR1) to predict metastasis in NPC and identify candidates that could benefit from induction chemotherapy (IC). Of these, adenylate kinase 4 (AK4) is a potent oncogene involved in the malignant progression of a variety of tumors. This study investigated the expression and mechanism of action of AK4, a member of the AK family of enzymes, in NPC. Quantitative real-time PCR, western blotting, and immunohistochemistry revealed that AK4 was upregulated in NPC and correlated with metastasis and chemoresistance. Stable ectopic overexpression of AK4 in NPC cell lines conferred resistance to taxol-induced apoptosis, promoted the migration, invasion, and EMT phenotype, and induced IL-1β secretion by activating the NLRP3 signaling pathway; knockdown of AK4 had the opposite effects. Mechanistically, AK4 co-localized with NNT, upregulated NLRP3 and IL-1β, and consequently altered NPC cell metastasis and chemoresistance. AK4 may play a role in the development of NPC and represent a potential therapeutic target.

MeSH terms

  • Adenylate Kinase* / genetics
  • Adenylate Kinase* / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-1beta / metabolism
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Nasopharyngeal Carcinoma* / drug therapy
  • Nasopharyngeal Carcinoma* / genetics
  • Nasopharyngeal Carcinoma* / metabolism
  • Nasopharyngeal Carcinoma* / pathology
  • Nasopharyngeal Neoplasms* / drug therapy
  • Nasopharyngeal Neoplasms* / genetics
  • Nasopharyngeal Neoplasms* / metabolism
  • Nasopharyngeal Neoplasms* / pathology
  • Neoplasm Metastasis
  • Paclitaxel / pharmacology
  • Signal Transduction

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Adenylate Kinase
  • NLRP3 protein, human
  • Paclitaxel
  • Interleukin-1beta