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Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA
Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidenc...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Pharmacology and Experimental Therapeutics
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626644/ https://www.ncbi.nlm.nih.gov/pubmed/34312217 http://dx.doi.org/10.1124/molpharm.121.000297 |
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author | Fermaintt, Charles S. Takahashi-Ruiz, Leila Liang, Huiyun Mooberry, Susan L. Risinger, April L. |
author_facet | Fermaintt, Charles S. Takahashi-Ruiz, Leila Liang, Huiyun Mooberry, Susan L. Risinger, April L. |
author_sort | Fermaintt, Charles S. |
collection | PubMed |
description | Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biologic hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects. Our data demonstrate that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, induces cGAS-STING–dependent expression of interferon-β in both myeloid and TNBC cells. Activation of the cGAS-STING pathway by eribulin was further found to be mediated by the accumulation of cytoplasmic mitochondrial DNA. Together, these findings provide mechanistic insight into how eribulin can induce innate immune signaling independent of its antimitotic or cytotoxic effects. SIGNIFICANCE STATEMENT: Microtubule-targeting agents (MTAs) are often used in the treatment of breast cancer and have been used in combination with immune checkpoint inhibitors to improve efficacy. Although all clinically approved MTAs share an antimitotic mechanism of action, their distinct effects on interphase microtubules can promote differential downstream signaling consequences. This work shows that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, activates the cGAS-STING innate immune signaling pathway through the accumulation of mitochondrial DNA in the cytoplasm. |
format | Online Article Text |
id | pubmed-8626644 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The American Society for Pharmacology and Experimental Therapeutics |
record_format | MEDLINE/PubMed |
spelling | pubmed-86266442022-10-01 Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA Fermaintt, Charles S. Takahashi-Ruiz, Leila Liang, Huiyun Mooberry, Susan L. Risinger, April L. Mol Pharmacol Articles Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biologic hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects. Our data demonstrate that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, induces cGAS-STING–dependent expression of interferon-β in both myeloid and TNBC cells. Activation of the cGAS-STING pathway by eribulin was further found to be mediated by the accumulation of cytoplasmic mitochondrial DNA. Together, these findings provide mechanistic insight into how eribulin can induce innate immune signaling independent of its antimitotic or cytotoxic effects. SIGNIFICANCE STATEMENT: Microtubule-targeting agents (MTAs) are often used in the treatment of breast cancer and have been used in combination with immune checkpoint inhibitors to improve efficacy. Although all clinically approved MTAs share an antimitotic mechanism of action, their distinct effects on interphase microtubules can promote differential downstream signaling consequences. This work shows that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, activates the cGAS-STING innate immune signaling pathway through the accumulation of mitochondrial DNA in the cytoplasm. The American Society for Pharmacology and Experimental Therapeutics 2021-10 2021-10 /pmc/articles/PMC8626644/ /pubmed/34312217 http://dx.doi.org/10.1124/molpharm.121.000297 Text en Copyright © 2021 by The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the CC BY Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Articles Fermaintt, Charles S. Takahashi-Ruiz, Leila Liang, Huiyun Mooberry, Susan L. Risinger, April L. Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title | Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title_full | Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title_fullStr | Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title_full_unstemmed | Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title_short | Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |
title_sort | eribulin activates the cgas-sting pathway via the cytoplasmic accumulation of mitochondrial dna |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626644/ https://www.ncbi.nlm.nih.gov/pubmed/34312217 http://dx.doi.org/10.1124/molpharm.121.000297 |
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