Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells

Free Radic Res. 2022 May-Jun;56(5-6):398-410. doi: 10.1080/10715762.2022.2131551. Epub 2022 Oct 13.

Abstract

Melittin is a natural polypeptide present in bee venom, with significant anti-tumor activity. Melittin has been reported to induce cell death in lung carcinoma cell line A549 cells, suggesting an excellent potential for treating lung cancer. However, the core mechanism underlying melittin-induced cell death in A549 cells remains unclear. This work reports that melittin induces reactive oxygen species (ROS) burst, upregulates intracellular Fe2+ levels, disrupts the glutathione-glutathione peroxidase 4 antioxidant system, and increases lipid peroxide accumulation, eventually inducing cell death, indicating that ferroptosis may be involved in the antitumor effects of melittin in A549 cells. Furthermore, A549 cells treated with the ferroptosis inhibitors ferrostatin-1 and deferoxamine demonstrated that these inhibitors could reverse the cell death induced by melittin, further confirming that melittin induces A549 cell death via ferroptosis. Furthermore, the results also illustrated that melittin activated the endoplasmic reticulum (ER) stress-CHOP (C/EBP homologous protein) apoptotic signal, closely associated with high-level intracellular ROS. The ER stress inhibitor, 4-Phenylbutyric acid, was used to confirm that ER stress-CHOP apoptotic signaling is another molecular mechanism of melittin-induced A549 cell death. Thus, our results demonstrate that ferroptosis and ER stress-CHOP signaling are key molecular mechanisms of melittin-induced cell death in lung cancer.

KEY POLICY HIGHLIGHTSMelittin upregulates intracellular Fe2+ levels, leading to the accumulation of lipid peroxides in A549 cells.Melittin disrupts the glutathione-glutathione peroxidase 4 antioxidant system in A549 cells.Melittin induces activation of endoplasmic reticulum stress-C/EBP homologous protein apoptosis signal.Ferroptosis and ER stress are the core molecular mechanisms underlying melittin-induced cell death in A549 cells.

Keywords: A549 cells; ER stress; Ferroptosis; Melittin; reactive oxygen species (ROS).

MeSH terms

  • A549 Cells
  • Antineoplastic Agents* / pharmacology
  • Antioxidants / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress
  • Ferroptosis*
  • Glutathione / pharmacology
  • Humans
  • Lung Neoplasms* / pathology
  • Melitten / pharmacology
  • Melitten / therapeutic use
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Reactive Oxygen Species / metabolism
  • Transcription Factor CHOP / metabolism

Substances

  • Reactive Oxygen Species
  • Melitten
  • Antioxidants
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Antineoplastic Agents
  • Transcription Factor CHOP
  • Glutathione