Journal article
Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles
PLoS biology, Vol.21(10), e3002339
10/26/2023
DOI: 10.1371/journal.pbio.3002339
PMCID: PMC10602348
PMID: 37883329
Abstract
Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.
Details
- Title: Subtitle
- Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles
- Creators
- Amber S Zhou - University of Wisconsin–MadisonJohn B Tucker - University of Wisconsin–MadisonChristina M Scribano - University of Wisconsin–MadisonAndrew R Lynch - University of Wisconsin–MadisonCaleb L Carlsen - University of Wisconsin–MadisonSophia T Pop-Vicas - University of Wisconsin–MadisonSrishrika M Pattaswamy - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin–MadisonBeth A Weaver - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.21(10), e3002339
- DOI
- 10.1371/journal.pbio.3002339
- PMID
- 37883329
- PMCID
- PMC10602348
- NLM abbreviation
- PLoS Biol
- ISSN
- 1544-9173
- eISSN
- 1545-7885
- Grant note
- T32 CA009135 / NCI NIH HHS F31 CA254247 / NCI NIH HHS T32 GM141013 / NIGMS NIH HHS T32 HG002760 / NHGRI NIH HHS T32 GM008688 / NIGMS NIH HHS P30 CA014520 / NCI NIH HHS R01 CA234904 / NCI NIH HHS
- Language
- English
- Date published
- 10/26/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701253302771
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