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ORIGINAL RESEARCH article
Front. Mol. Biosci.
Sec. Metabolomics
Volume 11 - 2024 |
doi: 10.3389/fmolb.2024.1520876
Metabolic Consequences of Erastin-induced Ferroptosis in Human Ovarian Cancer Cells: An Untargeted Metabolomics Study
Provisionally accepted- National Institute of Environmental Health Sciences (NIH), Durham, United States
Ovarian cancer has been difficult to cure due to acquired or intrinsic resistance and therefore, newer or more effective drugs/approaches are needed for a successful treatment in the clinic. Erastin (ER), a ferroptosis inducer, kills tumor cells by generating and accumulating reactive oxygen species (ROS) within the cell, resulting in an irondependent oxidative damage-mediated ferroptotic cell death. We have utilized human ovarian cancer cell lines, OVCAR-8 and its adriamycin-selected, multi-drug resistance protein (MDR1)-expressing NCI/ADR-RES, both equally sensitive to ER, to identify metabolic biomarkers of ferroptosis. Our studies showed that ER treatment rapidly depleted cellular glutathione and cysteine and enhanced formation of ophthalamate (OPH) in both cells. Opthalalmate has been proposed to be a biomarker of oxidative stress in cells. Our study also found significant decreases in cellular taurine, a natural antioxidant in cells. Additionally, we found that ER treatment decreased cellular levels of NAD+/NADP+, carnitines and glutamine/glutamate in both cells, suggesting significant oxidative stress, decrease in energy production, and cellular and mitochondrial disfunctions, leading to cell death. Our studies identified several potential biomarkers of ER-induced ferroptosis including OPH, taurine, NAD+, NADP+ and glutamate in ovarian cancer cells. Identifying specific metabolic biomarkers that are predictive of whether a cancer is susceptible to ferroptosis will help us devise more successful treatment modalities.
Keywords: Ferroptosis, Biomarkers, Ovarian Cancer, Erastin, Oxidative Stress. Abbreviation Used: ER, Erastin, VADC, voltage-dependent anion channel, Xc-, glutamate/cystine antiporter, ROS, Reactive Oxygen Species, GPX4, glutathione peroxidase 4, MDR1, multi-drug resistance1, OVCAR-8, (W), NCI/ADR-RES, (R)
Received: 31 Oct 2024; Accepted: 24 Dec 2024.
Copyright: © 2024 Sinha, Kirkwood-Donelson, Jarmusch, Bortner and Merrick. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Birandra K Sinha, National Institute of Environmental Health Sciences (NIH), Durham, United States
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