Abstract
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 STATEMENTMicrotubule-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.
Highlights
At 24 hours, we evaluated the effects of both drugs on cytokine expression and found that eribulin was distinct from paclitaxel, in its induction of IFNb and interferon-stimulated gene (ISG) in THP-1 cells, suggesting mechanistic differences between these microtubule-targeting agent (MTA) that cannot be strictly attributed to their shared antimitotic and apoptotic effects at this time point (Supplemental Fig. 1A)
Eribulin promotes cytoplasmic accumulation of mtDNA. (A) quantitative real time polymerase chain reaction (qRT-PCR) analysis of relative abundance of genomic DNA (ACTb, glycerol-3-phosphate dehydrogenase (GAPDH), hypoxanthine-guanine phosphoribosyltransferase (HPRT), phosphoglycerate kinase 1 (PGK), ribosomal protein S18 (RPS18), and TATA-binding protein (TBP)) and mitochondrial DNA (ATP6, ATP8, COX-1, ND1, ND4, and ND6) sequences present in the cytoplasm of HCC1937 cells treated with 100 nM eribulin (ERB) for 6 hours
Significance determined by vehicle-compared two-way ANOVA with Tukey’s post hoc test compared with vehicle. (F) COX-1 mRNA in control and ethidium bromide cultured (Rho0) HCC1937 cells treated with 100 nM eribulin for 2 or 6 hours as compared with DMSO
Summary
Postdoctoral training is supported by the US National Institutes of Health National Institute of General Medical Sciences K12 [Grant GM111726 (to C.S.F.)]. The flow cytometry core facility is supported by the University of Texas Health Science Center San Antonio Mays Cancer Center P30 Cancer Center Support Grant [NIH-NCI P30 CA054174] and the National Center for Advancing Translational Sciences, National Institutes of Health [Grant UL1 TR002645]. Eisai Inc. holds the intellectual property of eribulin mesylate.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
