# Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis

## TL;DR

Knocking down TOP2A makes ovarian cancer cells more sensitive to cisplatin by triggering cell death and blocking cancer spread through a specific molecular pathway.

## Contribution

This study reveals TOP2A as a new therapeutic target for cisplatin-resistant ovarian cancer by linking it to ferroptosis and EMT via the TP53/GPX4/SLC7A11 axis.

## Key findings

- TOP2A is highly expressed in cisplatin-resistant ovarian cancer and linked to poor prognosis.
- TOP2A knockdown increases cisplatin sensitivity and inhibits cancer progression via ferroptosis and EMT suppression.
- TOP2A interacts directly with TP53, regulating the GPX4/SLC7A11 axis to control resistance mechanisms.

## Abstract

Cisplatin resistance is a major challenge in ovarian cancer therapy, particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase IIα (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in ovarian cancer cisplatin resistance remain unclear.

TOP2A expression was detected in HGSOC tissues and cisplatin-resistant cells (SKOV3-DDP, OVCAR3-DDP). Functional assays combined with TOP2A knockdown evaluated cisplatin sensitivity and malignant phenotypes (proliferation, invasion, migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214302) validated TOP2A’s role in cisplatin resistance, prognostic value, and associations with TP53, GPX4, SLC7A11. Molecular docking/Co-IP confirmed TOP2A-TP53 interaction. Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation of ferroptosis and EMT, and an in vivo xenograft tumor model validated these findings.

TOP2A is highly expressed in HGSOC tissues and cisplatin-resistant cells, with high levels strongly associated with tumor progression (advanced stage, high grade, lymph node metastasis) and poor prognosis. RNA-seq shows TOP2A correlates with TP53, GPX4, SLC7A11.GEO dataset analysis confirms all four associate with cisplatin resistance. SLC7A11 and TOP2A are effective resistance biomarkers, and high TOP2A predicts shorter progression-free survival. Molecular assays verify direct TOP2A-TP53 interaction. Functional experiments reveal TOP2A knockdown enhances cisplatin sensitivity, inhibits malignancy, activates ferroptosis, and suppresses EMT via the TP53/GPX4/SLC7A11 axis. This effect is reversed by Fer-1 or TP53 knockdown, with mechanisms validated in vivo.

TOP2A represents a potential prognostic biomarker and therapeutic target for cisplatin resistance in ovarian cancer (OC), as it regulates ferroptosis and EMT via the TP53/GPX4/SLC7A11 axis, which is mediated by its direct interaction with TP53. This thus provides a novel direction for treating cisplatin-resistant OC.