DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells

Int J Mol Sci. 2021 Jan 3;22(1):420. doi: 10.3390/ijms22010420.

Abstract

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.

Keywords: death-associated protein 3; ionizing radiation; lung adenocarcinoma; mitochondria; radiosensitivity; retinoic acid-inducible gene-I-like receptor.

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology*
  • Adenocarcinoma of Lung / radiotherapy
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Proliferation
  • DEAD Box Protein 58
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / radiotherapy
  • Poly I-C / pharmacology*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Radiation, Ionizing*
  • Receptors, Immunologic / agonists*
  • Tumor Cells, Cultured

Substances

  • Apoptosis Regulatory Proteins
  • DAP3 protein, human
  • RNA-Binding Proteins
  • Receptors, Immunologic
  • RIGI protein, human
  • DEAD Box Protein 58
  • Poly I-C