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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...

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Autores principales: Fermaintt, Charles S., Takahashi-Ruiz, Leila, Liang, Huiyun, Mooberry, Susan L., Risinger, April L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Pharmacology and Experimental Therapeutics 2021
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.
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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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