Survival of cancer cells following taxol-induced apoptosis is supported by ZEB1-mediated ferroptosis sensitivity
4 affiliations
- 1Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, BC Canada
- 2Faculty of Medicine, University of British Columbia, Vancouver, BC Canada
- 3Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA USA
- 4Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC Canada
Abstract
Chemotherapy remains the mainstay treatment of many solid cancers; however, resistance and recurrence compromise patient outcomes. We investigated chemotherapy resistance mechanisms in Triple Negative Breast Cancer (TNBC) by examining cells that survive chemotherapy-induced apoptotic caspase activation. Using a biosensor that permanently labels cells surviving executioner caspase activation with GFP, we identified a GFP+ population that survives transient paclitaxel treatment. These GFP+ cells display a stem-like invasive phenotype, altered mitochondrial metabolism, and increased drug resistance. Metabolomics profiling identified defects in TCA cycle metabolites and accumulation of polyunsaturated fatty acids (PUFAs). Mechanistically, surviving GFP+ cells exhibited Epithelial to Mesenchymal Transition (EMT) and ZEB1-regulated repression of GPX4 expression, resulting in increased sensitivity to ferroptotic cell death. Consistent with this, transforming growth factor- beta induced EMT also suppressed GPX4 and increased ferroptosis sensitivity in Normal Mouse Mammary epithelial cells. ZEB1 knockdown strongly reduced the GFP+ surviving fraction, identifying ZEB1 as a key regulator of apoptotic survival. Supplementation with arachidonic acid restored survival in ZEB1 knockdown cells, while the ferroptosis-protective drug, Ferrostatin-1, prevented the accumulation of GFP+ survivors, demonstrating that ferroptosis sensitivity is required for the survival of TNBC cells from chemotherapy-induced apoptosis. Together, these findings reveal a previously unrecognized link between ferroptosis and apoptosis and identify potential biomarkers and therapeutic vulnerabilities in a subset of chemotherapy-resistant TNBC.
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BibTeX
@article{hausman2026survival,
title = {{Survival of cancer cells following taxol-induced apoptosis is supported by ZEB1-mediated ferroptosis sensitivity}},
author = {Rachel Hausman and Wells S. Brown and Shannon J. Awrey and Hossein Tavakoli and Denise J. Montell and Paul C. McDonald and Shoukat Dedhar},
journal = {Cell Death \& Disease},
year = {2026},
month = sep,
doi = {10.1038/s41419-026-09242-7},
url = {https://doi.org/10.1038/s41419-026-09242-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Survival of cancer cells following taxol-induced apoptosis is supported by ZEB1-mediated ferroptosis sensitivity
AU - Rachel Hausman
AU - Wells S. Brown
AU - Shannon J. Awrey
AU - Hossein Tavakoli
AU - Denise J. Montell
AU - Paul C. McDonald
AU - Shoukat Dedhar
PY - 2026
DA - 2026/09/02
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09242-7
UR - https://doi.org/10.1038/s41419-026-09242-7
AB - Chemotherapy remains the mainstay treatment of many solid cancers; however, resistance and recurrence compromise patient outcomes. We investigated chemotherapy resistance mechanisms in Triple Negative Breast Cancer (TNBC) by examining cells that survive chemotherapy-induced apoptotic caspase activation. Using a biosensor that permanently labels cells surviving executioner caspase activation with GFP, we identified a GFP+ population that survives transient paclitaxel treatment. These GFP+ cells display a stem-like invasive phenotype, altered mitochondrial metabolism, and increased drug resistance. Metabolomics profiling identified defects in TCA cycle metabolites and accumulation of polyunsaturated fatty acids (PUFAs). Mechanistically, surviving GFP+ cells exhibited Epithelial to Mesenchymal Transition (EMT) and ZEB1-regulated repression of GPX4 expression, resulting in increased sensitivity to ferroptotic cell death. Consistent with this, transforming growth factor- beta induced EMT also suppressed GPX4 and increased ferroptosis sensitivity in Normal Mouse Mammary epithelial cells. ZEB1 knockdown strongly reduced the GFP+ surviving fraction, identifying ZEB1 as a key regulator of apoptotic survival. Supplementation with arachidonic acid restored survival in ZEB1 knockdown cells, while the ferroptosis-protective drug, Ferrostatin-1, prevented the accumulation of GFP+ survivors, demonstrating that ferroptosis sensitivity is required for the survival of TNBC cells from chemotherapy-induced apoptosis. Together, these findings reveal a previously unrecognized link between ferroptosis and apoptosis and identify potential biomarkers and therapeutic vulnerabilities in a subset of chemotherapy-resistant TNBC.
SN - 2041-4889
ER -