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<p>Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP) with increased expression of type&#xa0;I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.</p>

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VPS34-IN1 potentiates STING-dependent activation in human CAL-1 cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月24日

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  • Paulo Antas,
  • Mariana D. Machado,
  • Fátima Leite-Pinheiro,
  • Daniela Barros,
  • Carlota Ramalhinho,
  • Andreia Mendes,
  • Beatriz H. Ferreira,
  • Daniela Carvoeiro,
  • Luís F. Mendes,
  • Marisa Reverendo,
  • Iola F. Duarte,
  • Miwako Narita,
  • Bing Su,
  • Rafael J. Argüello,
  • Beatrice Nal,
  • Philippe Pierre,
  • Catarina R. Almeida,
  • Evelina Gatti

摘要

Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP) with increased expression of type I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.