Txn-Txnrd1 system supports redox rewiring during polyaneuploid transition and protects giant cancer cells at new redox homeostasis
- 1University of Lodz
Abstract
Polyaneuploid giant cells (PGCC), which occur more frequently in TP53-mutant tumors, are recognized as a driver of tumor recurrence and therapy resistance, but the mechanisms supporting their survival remain largely unknown. Our results indicate that polyaneuploid transition and subsequent PGCC maturation in drug-resistant phenotypes are associated with redox rewiring that shifts cellular homeostasis into mild pro-oxidative condition. These are accompanied by increased transcription of genes involved in protection against elevated reactive oxygen species and glutathione-dependent xenobiotic detoxification such as TXN, PRDX2/5, GPX1, and GSTP1/GSTO1. Functional studies provided evidence on the crucial role of Txn-Txnrd1 system in maintaining PGCC viability and their adaptation to increased level of reactive oxygen species. Pharmacological targeting of Txn or Txnrd1 as well as their silencing caused a decline in thiol content followed by further redox imbalance, which led to massive death of PGCC. Analysis of clinical datasets revealed direct and relatively strong link between transcription of TP53 and TXN or TXNRD1. Tumors with TP53low/TXNhigh or TP53low/TXNRD1high were associated with considerably poorer patient outcome, whereas elevated transcription of both TXN and TXNRD1 predicted reduced response to chemotherapy in glioblastoma and intestinal cancer. Concluding, Txn-Txnrd1 system enables PGCCs to tolerate pro-oxidative condition, thereby creating a therapeutically exploitable redox vulnerability of these cells, where Txnrd1 emerges as a potential target candidate to overcome PGCC-driven chemoresistance.
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BibTeX
@misc{kolaczmilewska2026txntxnrd1,
title = {{Txn-Txnrd1 system supports redox rewiring during polyaneuploid transition and protects giant cancer cells at new redox homeostasis}},
author = {K. Kolacz-Milewska and K. Gronkowska and S. Michlewska and M. Absenger and E. Froehlich and A. Robaszkiewicz},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.746985},
url = {https://www.biorxiv.org/content/10.64898/2026.08.27.746985v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Txn-Txnrd1 system supports redox rewiring during polyaneuploid transition and protects giant cancer cells at new redox homeostasis
AU - K. Kolacz-Milewska
AU - K. Gronkowska
AU - S. Michlewska
AU - M. Absenger
AU - E. Froehlich
AU - A. Robaszkiewicz
PY - 2026
DA - 2026/08/27
PB - bioRxiv
DO - 10.64898/2026.08.27.746985
UR - https://www.biorxiv.org/content/10.64898/2026.08.27.746985v2
AB - Polyaneuploid giant cells (PGCC), which occur more frequently in TP53-mutant tumors, are recognized as a driver of tumor recurrence and therapy resistance, but the mechanisms supporting their survival remain largely unknown. Our results indicate that polyaneuploid transition and subsequent PGCC maturation in drug-resistant phenotypes are associated with redox rewiring that shifts cellular homeostasis into mild pro-oxidative condition. These are accompanied by increased transcription of genes involved in protection against elevated reactive oxygen species and glutathione-dependent xenobiotic detoxification such as TXN, PRDX2/5, GPX1, and GSTP1/GSTO1. Functional studies provided evidence on the crucial role of Txn-Txnrd1 system in maintaining PGCC viability and their adaptation to increased level of reactive oxygen species. Pharmacological targeting of Txn or Txnrd1 as well as their silencing caused a decline in thiol content followed by further redox imbalance, which led to massive death of PGCC. Analysis of clinical datasets revealed direct and relatively strong link between transcription of TP53 and TXN or TXNRD1. Tumors with TP53low/TXNhigh or TP53low/TXNRD1high were associated with considerably poorer patient outcome, whereas elevated transcription of both TXN and TXNRD1 predicted reduced response to chemotherapy in glioblastoma and intestinal cancer. Concluding, Txn-Txnrd1 system enables PGCCs to tolerate pro-oxidative condition, thereby creating a therapeutically exploitable redox vulnerability of these cells, where Txnrd1 emerges as a potential target candidate to overcome PGCC-driven chemoresistance.
ER -