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Spatiotemporally Controlled Nuclear Translocation of Guests in Living Cells Using Caged Molecular Glues as Photoactivatable Tags
Published on: January 17, 2019
Cytoplasmic relocation of nuclear Ku70 by Bruceine A augments cGAS-STING pathway-mediated anti-tumor immunity
Kai Huang1, Zhaohui Tang1, Qin Gong1
1State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Science, Nanjing University, Nanjing 210093, China.
Abstract:
DNA-damaging agents combined with agonists of the cGAS-STING pathway can effectively suppress colorectal cancer (CRC) by inducing cancer cell death and eliciting an antitumor immune response. In this study, we demonstrate that the natural compound Bruceine A (BA) inhibits CRC progression through a dual mechanism involving nuclear-to-cytoplasmic translocation of Ku70. Cytoplasmic Ku70 loses its canonical DNA repair function while simultaneously enhancing its interaction with cGAS, leading to increased cGAS oligomerization and elevated levels of double-stranded DNA (dsDNA), both of which amplify cGAS-STING signaling. Furthermore, Bruceine A-mediated Ku70 translocation exacerbates DNA damage accumulation, further enhancing tumor immunogenicity. In the murine CRC model, Bruceine A significantly inhibited tumor growth and enhanced tumor sensitivity to chemotherapy, radiotherapy, and anti-PD-1 treatment. Notably, genetic ablation of STING and CD8+ T cells in mice substantially abolished the antitumor effects of Bruceine A, confirming its reliance on cGAS-STING activation and adaptive immunity. Our findings establish Ku70 as a novel therapeutic target in CRC, where its subcellular redistribution disrupts genomic stability and bridges innate immune activation, synergistically promoting tumor cell death and antitumor immunity. Modulating Ku70 localization thus represents a promising strategy to enhance CRC treatment.
Insights
Bruceine A suppresses colorectal cancer (CRC) by moving Ku70 protein, boosting the immune system's attack on tumors. This natural compound enhances existing cancer treatments and shows promise for CRC therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Colorectal cancer (CRC) can be suppressed by DNA-damaging agents and cGAS-STING pathway agonists.
- The natural compound Bruceine A (BA) exhibits potential in inhibiting CRC progression.
Purpose of the Study:
- To investigate the dual mechanism of Bruceine A in inhibiting CRC progression.
- To explore the role of Ku70 translocation in cGAS-STING signaling and CRC immunogenicity.
- To evaluate the therapeutic potential of Bruceine A in combination with standard CRC treatments.
Main Methods:
- Investigated the effect of Bruceine A on Ku70 subcellular localization.
- Assessed the impact of Ku70 translocation on cGAS-STING pathway activation and dsDNA levels.
- Evaluated Bruceine A's efficacy in a murine CRC model, alone and in combination with chemotherapy, radiotherapy, and anti-PD-1 therapy.
- Utilized genetic ablation of STING and CD8+ T cells to confirm the mechanism of action.
Main Results:
- Bruceine A induced nuclear-to-cytoplasmic translocation of Ku70, impairing DNA repair and enhancing cGAS interaction.
- This translocation amplified cGAS-STING signaling and increased dsDNA levels, exacerbating DNA damage and tumor immunogenicity.
- Bruceine A significantly inhibited tumor growth and sensitized CRC to various treatments in mice.
- Antitumor effects were dependent on STING and CD8+ T cells, highlighting the role of adaptive immunity.
Conclusions:
- Ku70 is a novel therapeutic target in CRC, with its subcellular redistribution disrupting genomic stability and activating innate immunity.
- Bruceine A synergistically promotes tumor cell death and antitumor immunity by modulating Ku70 localization.
- Targeting Ku70 localization offers a promising strategy to enhance CRC treatment efficacy.
