Ferroptosis Inducers in Thyroid Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Papillary thyroid carcinoma (PTC) progression is linked to reduced survival.
• Glutathione (GSH) metabolism influences tumor resistance and progression.
• Glutathione peroxidase 4 (GPX4) is crucial in preventing lipid peroxidation and regulating ferroptosis.

Purpose of the Study:

• To investigate the differential ferroptosis effects of GPX4 inhibitors in thyroid cancer cell and 3-D spheroid in vitro models.
• To analyze the impact of GPX4 inhibition on PTC cells with specific mutations (BRAF, RAS, TERT promoter, PIK3CA).

Main Methods:

• Assessed GPX4 inhibitor effects on ferroptosis, proliferation, oxidative stress, and signaling pathways.
• Utilized Western blot, GSH/GSSG levels, ROS induction, RT-qPCR, migration, and proliferation assays.
• Examined differential responses in monolayer vs. 3-D spheroid models.

Main Results:

• GPX4 inhibitors induced ferroptosis, increased reactive oxygen species (ROS), and depleted GSH in PTC cells.
• Tumor cell migration was arrested, DNA damage increased, and mTOR/DNA repair pathways were suppressed.
• Differential responses to DNA damage and GPX4 levels were observed between 3-D spheroids and monolayer cells.

Conclusions:

• GPX4 inhibition robustly and differentially activates ferroptosis in both monolayer and 3-D thyroid cancer models.
• This study is the first to detail differential GPX4 inhibitor effects across diverse PTC mutational signatures.
• A novel mechanism for GPX4 inhibition in preclinical thyroid cancer models was identified, with potential for treating advanced, therapy-resistant cancers.