Ferroptosis Inducers in Thyroid Cancer

• Published in: World journal of surgery 2023-02, Vol.47 (2), p.371-381
• Main Authors: Sekhar, Konjeti R., Cyr, Sriram, Baregamian, Naira
• Format: Article
• Language: English
• Subjects: Abdominal Surgery; Cancer; Cardiac Surgery; Cell death; Cell membranes; Cell migration; Damage; Deoxyribonucleic acid; Depletion; DNA; DNA damage; DNA repair; Ferroptosis; General Surgery; Glutathione; Glutathione peroxidase; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Humans; In vitro methods and tests; Inhibitors; Lipid peroxidation; Lipids; Medicine; Medicine & Public Health; Metabolism; Monolayers; Mutation; Original Scientific Report; Oxidation; Oxidative stress; Papillary thyroid carcinoma; Peroxidase; Peroxidation; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Reactive Oxygen Species - metabolism; Spheroids; Surgery; Thoracic Surgery; Three dimensional models; Thyroid; Thyroid cancer; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - genetics; TOR protein; Tumor cells; Tumors; Vascular Surgery
• ISSN: 0364-2313; 1432-2323
• DOI: 10.1007/s00268-022-06738-z

Purpose Papillary thyroid carcinoma (PTC) progression imparts reduced patient survival. Tumor resistance and progression can be influenced by Glutathione (GSH) metabolism. Glutathione peroxidase 4 (GPX4) regulates GSH oxidation to prevent lipid peroxidation of cell membranes during increased oxidative stress and regulates ferroptosis cell death pathway in tumor cells. This study examines the differential ferroptosis effects by GPX4 inhibitors in thyroid cancer cell and 3-D spheroid in vitro models. Materials and methods We examined differential effects of GPX4 inhibitors on PTC cells (K1, MDA-T32, MDA-T68) with BRAF and RAS mutations, and TERT promoter and PIK3CA co-mutations. The effects of GPX4 inhibitors on ferroptosis activation, proliferation, oxidative stress, and activation of signaling pathways were assessed by Western blot, total (GSH) and oxidized glutathione (GSSG) levels, ROS induction, RT-qPCR, migration, and proliferation assays. Results GPX4 inhibitors induced ferroptosis, rising ROS, GSH depletion, arrested tumor cell migration, increased DNA damage, suppressed mTOR pathway and DNA repair response in PTC cells in vitro. Differential responses to DNA damage and GPX4 levels were observed between 3-D PTC spheroids and thyroid cancer cells in a monolayer model. Conclusion Effective GPX4 inhibition with various inhibitors induced a robust but differential activation of ferroptosis in monolayer thyroid tumor cell and 3-D PTC spheroid models. Our study is the first of its kind to determine the differential effects of GPX4 inhibitors on thyroid cancer cells with diverse mutational signatures. We have identified a novel mechanism of action of GPX4 inhibition in preclinical in vitro models of thyroid cancer that can be further exploited for therapeutic benefit in advanced therapy-resistant thyroid cancers.