PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis
Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on ce...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/5/691 |
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| author | Lorenzo Monteleone Andrea Speciale Giulia Elda Valenti Nicola Traverso Silvia Ravera Ombretta Garbarino Riccardo Leardi Emanuele Farinini Antonella Roveri Fulvio Ursini Claudia Cantoni Maria Adelaide Pronzato Umberto Maria Marinari Barbara Marengo Cinzia Domenicotti |
| author_facet | Lorenzo Monteleone Andrea Speciale Giulia Elda Valenti Nicola Traverso Silvia Ravera Ombretta Garbarino Riccardo Leardi Emanuele Farinini Antonella Roveri Fulvio Ursini Claudia Cantoni Maria Adelaide Pronzato Umberto Maria Marinari Barbara Marengo Cinzia Domenicotti |
| author_sort | Lorenzo Monteleone |
| collection | DOAJ |
| description | Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance. |
| first_indexed | 2024-03-10T11:53:55Z |
| format | Article |
| id | doaj.art-471d631c58894e88b0fdf5a7bf6233c5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T11:53:55Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-471d631c58894e88b0fdf5a7bf6233c52023-11-21T17:28:41ZengMDPI AGAntioxidants2076-39212021-04-0110569110.3390/antiox10050691PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating FerroptosisLorenzo Monteleone0Andrea Speciale1Giulia Elda Valenti2Nicola Traverso3Silvia Ravera4Ombretta Garbarino5Riccardo Leardi6Emanuele Farinini7Antonella Roveri8Fulvio Ursini9Claudia Cantoni10Maria Adelaide Pronzato11Umberto Maria Marinari12Barbara Marengo13Cinzia Domenicotti14General Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyMutagenesis and Cancer Prevention Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyHuman Anatomy Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyDepartment of Cardiovascular Medicine, IRCCS Humanitas Clinical and Research Center, Rozzano, 20089 Milan, ItalyDepartment of Pharmacy, University of Genoa, 16126 Genoa, ItalyDepartment of Pharmacy, University of Genoa, 16126 Genoa, ItalyDepartment of Molecular Medicine, University of Padua, 35122 Padua, ItalyDepartment of Molecular Medicine, University of Padua, 35122 Padua, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyGeneral Pathology Section, Department of Experimental Medicine, University of Genoa, 16126 Genoa, ItalyCancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance.https://www.mdpi.com/2076-3921/10/5/691cancer stem cellschemoresistanceglutathionelipid peroxidationZEB-1GPX4 |
| spellingShingle | Lorenzo Monteleone Andrea Speciale Giulia Elda Valenti Nicola Traverso Silvia Ravera Ombretta Garbarino Riccardo Leardi Emanuele Farinini Antonella Roveri Fulvio Ursini Claudia Cantoni Maria Adelaide Pronzato Umberto Maria Marinari Barbara Marengo Cinzia Domenicotti PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis Antioxidants cancer stem cells chemoresistance glutathione lipid peroxidation ZEB-1 GPX4 |
| title | PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis |
| title_full | PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis |
| title_fullStr | PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis |
| title_full_unstemmed | PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis |
| title_short | PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis |
| title_sort | pkcα inhibition as a strategy to sensitize neuroblastoma stem cells to etoposide by stimulating ferroptosis |
| topic | cancer stem cells chemoresistance glutathione lipid peroxidation ZEB-1 GPX4 |
| url | https://www.mdpi.com/2076-3921/10/5/691 |
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