FDFT1 Suppresses Ovarian Tumorigenesis and Overcomes Cisplatin Resistance by Activating Ferroptosis Through the NRF2/GPX4/SLC7A11 Axis
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Published on: March 15, 2024
Yu Jiang1, Pincheng Li2, Ximu Xiao2
1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Introduction:
Ovarian cancer's lethality stems from late-stage diagnosis and chemoresistance. Ferroptosis induction represents a promising strategy to overcome platinum resistance. Farnesyl diphosphate farnesyltransferase 1(FDFT1), a cholesterol metabolism enzyme with paradoxical roles in cancer, remains relatively underexplored in ovarian carcinogenesis and therapeutic resistance.
Method:
Multi-omics analyses of public datasets identified FDFT1's clinical relevance. Functional studies employed FDFT1-overexpressing ovarian cancer cells (SKOV3/ES-2) and cisplatin-resistant SKOV3/DDP models. Mechanistic evaluations included ferroptosis markers (Fe²⁺, MDA, GSH), NRF2/GPX4/SLC7A11 axis analysis, and xenograft experiments.
Results:
FDFT1 showed recurrent genomic loss and downregulation in ovarian tumors. Overexpression suppressed proliferation, migration, and invasion, while increasing apoptosis. FDFT1 activated ferroptosis via NRF2/GPX4/SLC7A11 axis suppression, elevating Fe²⁺, MDA, and ROS while depleting GSH. Cisplatin-resistant tumors exhibited FDFT1 downregulation, and overexpression of FDFT1 reversed drug resistance. Xenografts confirmed tumor growth suppression with ferroptosis activation.
Discussion:
Our findings establish FDFT1 as a tumor suppressor that induces ferroptosis via NRF2/GPX4/SLC7A11 inhibition in ovarian cancer. Restoring FDFT1 reverses cisplatin resistance, linking its downregulation to chemoresistance. This contrasts with its oncogenic roles in other cancers, highlighting context-dependent metabolic regulation. These findings position FDFT1 as a novel regulator of ferroptosis and a promising therapeutic target for overcoming chemoresistance in ovarian cancer.
Conclusion:
FDFT1 functions as a tumor suppressor by inducing iron-dependent lipid peroxidation through NRF2 pathway inhibition. Its restoration overcomes cisplatin resistance, positioning FDFT1 as both a promising biomarker and therapeutic target for chemoresistant ovarian cancer.
Insights
Farnesyl diphosphate farnesyltransferase 1 (FDFT1) acts as a tumor suppressor in ovarian cancer by inducing ferroptosis and overcoming cisplatin resistance. Restoring FDFT1 shows promise as a therapeutic strategy for chemoresistant ovarian cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ovarian cancer is often diagnosed late and develops chemoresistance, limiting treatment efficacy.
- Ferroptosis induction is a potential strategy to overcome platinum resistance in ovarian cancer.
- The role of Farnesyl diphosphate farnesyltransferase 1 (FDFT1) in ovarian cancer and its resistance mechanisms is not well understood.
Purpose of the Study:
- To investigate the role of FDFT1 in ovarian cancer development and chemoresistance.
- To explore FDFT1's mechanism in regulating ferroptosis and its potential as a therapeutic target.
Main Methods:
- Multi-omics analyses of public datasets to identify FDFT1's clinical relevance.
- Functional studies using ovarian cancer cell lines and cisplatin-resistant models.
- Mechanistic evaluations of ferroptosis markers and the NRF2/GPX4/SLC7A11 axis, including xenograft experiments.
Main Results:
- FDFT1 is recurrently lost and downregulated in ovarian tumors.
- FDFT1 overexpression suppresses tumor growth, migration, and invasion while promoting apoptosis.
- FDFT1 induces ferroptosis by suppressing the NRF2/GPX4/SLC7A11 axis, reversing cisplatin resistance in ovarian cancer models.
Conclusions:
- FDFT1 acts as a tumor suppressor in ovarian cancer by inducing ferroptosis via NRF2 pathway inhibition.
- Restoration of FDFT1 overcomes cisplatin resistance, identifying it as a potential biomarker and therapeutic target for chemoresistant ovarian cancer.
