Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells <i>in vitro</i> and <i>in vivo</i>

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Abstract

Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them – ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis. Ferroptosis is accompanied by peroxidation of polyunsaturated species of phosphatidylethanolamine (PE) to hydroperoxy- (-OOH) derivatives, which act as death signals. We demonstrate that RSL3-induced death of A375 melanoma cells in vitro was fully preventable by ferrostatin-1, suggesting their high susceptibility to ferroptosis. Treatment of A375 cells with RSL3 caused a significant accumulation of PE-(18:0/20:4-OOH) and PE-(18:0/22:4-OOH), the biomarkers of ferroptosis, as well as oxidatively truncated products - PE-(18:0/hydroxy-8-oxo-oct-6-enoic acid (HOOA) and PC-(18:0/HOOA). A significant suppressive effect of RSL3 on melanoma growth was observed in vivo (utilizing a xenograft model of inoculation of GFP-labeled A375 cells into immune-deficient athymic nude mice). Redox phospholipidomics revealed elevated levels of 18:0/20:4-OOH in RSL3-treated group vs controls. In addition, PE-(18:0/20:4-OOH) species were identified as major contributors to the separation of control and RSL3-treated groups, with the highest variable importance in projection predictive score. Pearson correlation analysis revealed an association between tumor weight and contents of PE-(18:0/20:4-OOH) (r = −0.505), PE-18:0/HOOA (r = −0.547) and PE 16:0-HOOA (r = −0.503). Thus, LC-MS/MS based redox lipidomics is a sensitive and precise approach for the detection and characterization of phospholipid biomarkers of ferroptosis induced in cancer cells by radio- and chemotherapy.

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Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Yulia Y. Tyurina

Apurva K. Srivastava

Valerian E. Kagan

Journal

Journal ID (nlm-ta): Redox Biol

Journal ID (iso-abbrev): Redox Biol

Title: Redox Biology

Publisher: Elsevier

ISSN (Electronic): 2213-2317

Publication date PMC-release: 28 February 2023

Publication date Collection: May 2023

Publication date (Electronic): 28 February 2023

Volume: 61

Electronic Location Identifier: 102650

Affiliations

[a ]Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA

[b ]Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA

[c ]Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA

[d ]Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

[e ]Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

[f ]The Wistar Institute, Philadelphia, PA, USA

[g ]Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

[h ]Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

Author notes

[∗ ]Corresponding author. Department of Environmental and Occupational Health, 130 De Soto St, Pittsburgh, PA, 15261, USA. kagan@ 123456pitt.edu

[∗∗ ]Corresponding author. Frederick National Laboratory for Cancer Research, 8560 Progress Drive, Frederick, MD, 21701, USA. srivastavaa4@ 123456mail.nih.gov

[∗∗∗ ]Corresponding author. Department of Environmental and Occupational Health, 130 De Soto St, Pittsburgh, PA, 15261, USA. yyt1@ 123456pitt.edu

Article

Publisher Item ID: S2213-2317(23)00051-4 Publisher ID: 102650

DOI: 10.1016/j.redox.2023.102650

PMC ID: 9996109

PubMed ID: 36870109

SO-VID: 9f8b65e8-7a62-4b23-9f02-e821a6a03ba8

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 29 December 2022

Date revision received : 19 February 2023

Date accepted : 27 February 2023

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