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Icaritin ameliorates extracellular microparticles-induced inflammatory pre-metastatic niche via modulating the
Shumei Tu1,2, Dengxuan Mao1,2, Mengxin Shi1,2
1Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Abstract:
The concept of the inflammatory pre-metastatic niche (PMN) provides a new and promising direction for the prevention and treatment of metastasis. The excessive activation of the GAS-STING signaling leads to augmented metastasis by promoting the formation of the inflammatory PMN. In this study, tumor-derived microparticles (MP) were used to establish the PMN model both in vitro and in vivo, and pro-inflammatory mediators were also employed to evaluate the effects of Icaritin (ICT). It was demonstrated that ICT could inhibit the pulmonary metastasis of B16BL6 melanoma cells in mice via interfering with PMN. The phosphorylation and dimerization of STING and its downstream signaling TBK1-IFNβ were proved to be diminished in the presence of ICT. Furthermore, we revealed that ICT suppressed the generation of pro-inflammatory PMN through conferring the inactivation of the STING signaling pathway. CETSA and DARTS assay also confirmed that STING tended to be a target for the action of ICT. Collectively, our findings highlight a new binding mechanism between STING and ICT for the inhibition of transduction of the STING signaling pathway, suggesting that pharmacological or therapeutic intervention of the STING-TBK1-IFNβ singling axis may serve as an effective strategy to prevent the progression of inflammatory PMN and lung metastasis.
Insights
Icaritin inhibits lung metastasis by targeting the STING signaling pathway, preventing the formation of inflammatory pre-metastatic niches (PMN). This discovery offers a new therapeutic strategy for cancer metastasis.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Metastasis remains a primary cause of cancer-related mortality.
- The inflammatory pre-metastatic niche (PMN) plays a crucial role in facilitating metastasis.
- GAS-STING signaling pathway activation promotes PMN formation and metastasis.
Purpose of the Study:
- To investigate the effect of Icaritin (ICT) on the formation of inflammatory PMN.
- To elucidate the mechanism by which ICT inhibits metastasis.
- To explore STING as a potential therapeutic target.
Main Methods:
- Established an inflammatory PMN model in vitro and in vivo using tumor-derived microparticles (MP).
- Administered ICT to B16BL6 melanoma-bearing mice to assess pulmonary metastasis.
- Analyzed STING signaling pathway components (STING, TBK1, IFNβ) phosphorylation and dimerization.
- Utilized CETSA and DARTS assays to confirm STING as a direct target of ICT.
Main Results:
- ICT significantly inhibited pulmonary metastasis of B16BL6 melanoma cells in mice.
- ICT treatment reduced the phosphorylation and dimerization of STING and its downstream signaling molecules.
- ICT suppressed the generation of pro-inflammatory PMN by inactivating the STING signaling pathway.
- Evidence confirmed STING as a direct binding target of ICT.
Conclusions:
- Icaritin effectively inhibits lung metastasis by targeting and inactivating the STING signaling pathway.
- This mechanism involves the suppression of inflammatory pre-metastatic niche formation.
- Targeting the STING-TBK1-IFNβ axis presents a promising therapeutic strategy for preventing metastasis.
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