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

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 i...

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Vydané v:Redox biology Ročník 61; s. 102650
Hlavní autori: 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 G., Parchment, Ralph E., Doroshow, James H., Bayir, Hulya, Srivastava, Apurva K., Kagan, Valerian E.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Netherlands Elsevier B.V 01.05.2023
Elsevier
Predmet:
A375 melanoma cells
Animals
Biomarkers
Cell Death
Chromatography, Liquid
Ferroptosis
Humans
Hydroperoxy-phosphatidylethanolamine
Lipid Peroxidation
Melanoma
Mice
Mice, Nude
Oxidation-Reduction
Redox lipidomics
Research Paper
Tandem Mass Spectrometry
Redox lipidomics
Biomarkers
Ferroptosis
Hydroperoxy-phosphatidylethanolamine
A375 melanoma cells
ISSN:2213-2317, 2213-2317
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
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ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2023.102650