EDN1 facilitates cisplatin resistance of non-small cell lung cancer cells by regulating the TNF signaling pathway

World J Surg Oncol. 2025 Mar 1;23(1):71. doi: 10.1186/s12957-025-03692-7.

Abstract

Background: Cisplatin (DDP) is a commonly utilized chemotherapeutic agent. Nevertheless, the development of resistance to DDP significantly diminishes the effectiveness of DDP-based chemotherapy in patients with non-small cell lung cancer (NSCLC). In this study, we investigated the impact of endothelin 1 (EDN1) on the resistance to DDP in NSCLC.

Methods: The proliferation, invasion, and migration of NSCLC cells were detected by cell counting kit-8 and Transwell migration and invasion assays. ELISA was performed to analyze the inflammatory cytokines concentrations. The related protein levels of tumor necrosis factor (TNF) signaling pathway were analyzed by Western blot. Besides, a xenograft tumor mice model was established to explore the role of EDN1 in vivo.

Results: The results showed that DDP-resistance upregulated EDN1 expression, cell viability, invasion, migration, and inflammation in NSCLC cells, while the results were reversed after EDN1 inhibition. EDN1 affected DDP-resistance of NSCLC by regulating TNF signaling pathway. Overexpression of TNF receptor-1 (TNFR1) reversed the decreased cell viability, invasion, migration, and inflammation induced by silencing EDN1 in A549/DDP cells. Moreover, silencing EDN1 inhibited tumor growth and the protein levels of EDN1 and TNFR1.

Conclusion: EDN1 promoted DDP resistance in NSCLC cells through the modulation of the TNF signaling pathway, suggesting a potential therapeutic intervention strategy for NSCLC.

Keywords: Cisplatin resistance; EDN1; Non-small cell lung cancer; TNF signaling pathway.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Cisplatin* / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Endothelin-1* / genetics
  • Endothelin-1* / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Signal Transduction* / drug effects
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha* / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • Cisplatin
  • Endothelin-1
  • Tumor Necrosis Factor-alpha
  • Antineoplastic Agents
  • Receptors, Tumor Necrosis Factor, Type I