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Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo

  1. Author:
    Tyurina, Yulia Y
    Kapralov, Alexandr A
    Tyurin, Vladimir A
    Shurin, Galina
    Amoscato, Andrew A
    Rajasundaram, Dhivyaa
    Tian, Hua
    Bunimovich, Yuri L
    Nefedova, Yulia
    Herrick,William
    Parchment,Ralph
    Doroshow, James H
    Bayir, Hulya
    Srivastava,Apurva
    Kagan, Valerian E

  2. Author Address

    Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: yyt1@pitt.edu., Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA., The Wistar Institute, Philadelphia, PA, USA., Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA., Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. Electronic address: srivastavaa4@mail.nih.gov., Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: kagan@pitt.edu.,
    1. Year: 2023
    2. Date: Feb 28
    3. Epub Date: 2023 02 28
  2. Journal: Redox Biology
    1. 61
    2. Pages: 102650
  4. Type of Article: Article
  5. Article Number: 102650
  1. 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. Copyright © 2023. Published by Elsevier B.V.

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  2. DOI: 10.1016/j.redox.2023.102650
  3. PMID: 36870109
  4. PMCID: PMC9996109
  5. PII : S2213-2317(23)00051-4

Library Notes

  1. Fiscal Year: FY2022-2023
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