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H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS

Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. This phenomenon can be attributed to the inherited high expression of antioxidant protein network. H-Ferr...

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Autores principales: Salatino, Alessandro, Aversa, Ilenia, Battaglia, Anna Martina, Sacco, Alessandro, Di Vito, Anna, Santamaria, Gianluca, Chirillo, Roberta, Veltri, Pierangelo, Tradigo, Giuseppe, Di Cello, Annalisa, Venturella, Roberta, Biamonte, Flavia, Costanzo, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875340/
https://www.ncbi.nlm.nih.gov/pubmed/31781333
http://dx.doi.org/10.1155/2019/3461251
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author Salatino, Alessandro
Aversa, Ilenia
Battaglia, Anna Martina
Sacco, Alessandro
Di Vito, Anna
Santamaria, Gianluca
Chirillo, Roberta
Veltri, Pierangelo
Tradigo, Giuseppe
Di Cello, Annalisa
Venturella, Roberta
Biamonte, Flavia
Costanzo, Francesco
author_facet Salatino, Alessandro
Aversa, Ilenia
Battaglia, Anna Martina
Sacco, Alessandro
Di Vito, Anna
Santamaria, Gianluca
Chirillo, Roberta
Veltri, Pierangelo
Tradigo, Giuseppe
Di Cello, Annalisa
Venturella, Roberta
Biamonte, Flavia
Costanzo, Francesco
author_sort Salatino, Alessandro
collection PubMed
description Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. This phenomenon can be attributed to the inherited high expression of antioxidant protein network. H-Ferritin is an important member of the antioxidant system due to its ability to store iron in a nontoxic form. Altered expression of H-Ferritin has been described in ovarian cancers; however, its functional role in cisplatin-based chemoresistance of this cancer type has never been explored. Here, we investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells. First, we characterized OVCAR3 and OVCAR8 cells for their relative ROS and H-Ferritin baseline amounts. OVCAR3 exhibited lower ROS levels compared to OVCAR8 and greater expression of H-Ferritin. In addition, OVCAR3 showed pronounced growth potential and survival accompanied by the strong activation of pERK/pAKT and overexpression of c-Myc and cyclin E1. When exposed to different concentrations of cisplatin, OVCAR3 were less sensitive than OVCAR8. At the lowest concentration of cisplatin (6 μM), OVCAR8 underwent a consistent apoptosis along with a downregulation of H-Ferritin and a consistent increase of ROS levels; on the other hand, OVCAR3 cells were totally unresponsive, H-Ferritin was almost unaffected, and ROS amounts met a slight increase. Thus, we assessed whether the modulation of H-Ferritin levels was able to affect the cisplatin-mediated cytotoxicity in both the cell lines. H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity to 6 μM cisplatin in resistant OVCAR3 cells. Conversely, forced overexpression of H-Ferritin significantly suppressed the cisplatin-mediated elevation of intracellular ROS subsequently leading to a reduced responsiveness in OVCAR8 cells. Overall, our findings suggest that H-Ferritin might be a key protein in cisplatin-based chemoresistance and that its inhibition may represent a potential approach for enhancing cisplatin sensitivity of resistant ovarian cancer cells.
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spelling pubmed-68753402019-11-28 H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS Salatino, Alessandro Aversa, Ilenia Battaglia, Anna Martina Sacco, Alessandro Di Vito, Anna Santamaria, Gianluca Chirillo, Roberta Veltri, Pierangelo Tradigo, Giuseppe Di Cello, Annalisa Venturella, Roberta Biamonte, Flavia Costanzo, Francesco Oxid Med Cell Longev Research Article Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. This phenomenon can be attributed to the inherited high expression of antioxidant protein network. H-Ferritin is an important member of the antioxidant system due to its ability to store iron in a nontoxic form. Altered expression of H-Ferritin has been described in ovarian cancers; however, its functional role in cisplatin-based chemoresistance of this cancer type has never been explored. Here, we investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells. First, we characterized OVCAR3 and OVCAR8 cells for their relative ROS and H-Ferritin baseline amounts. OVCAR3 exhibited lower ROS levels compared to OVCAR8 and greater expression of H-Ferritin. In addition, OVCAR3 showed pronounced growth potential and survival accompanied by the strong activation of pERK/pAKT and overexpression of c-Myc and cyclin E1. When exposed to different concentrations of cisplatin, OVCAR3 were less sensitive than OVCAR8. At the lowest concentration of cisplatin (6 μM), OVCAR8 underwent a consistent apoptosis along with a downregulation of H-Ferritin and a consistent increase of ROS levels; on the other hand, OVCAR3 cells were totally unresponsive, H-Ferritin was almost unaffected, and ROS amounts met a slight increase. Thus, we assessed whether the modulation of H-Ferritin levels was able to affect the cisplatin-mediated cytotoxicity in both the cell lines. H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity to 6 μM cisplatin in resistant OVCAR3 cells. Conversely, forced overexpression of H-Ferritin significantly suppressed the cisplatin-mediated elevation of intracellular ROS subsequently leading to a reduced responsiveness in OVCAR8 cells. Overall, our findings suggest that H-Ferritin might be a key protein in cisplatin-based chemoresistance and that its inhibition may represent a potential approach for enhancing cisplatin sensitivity of resistant ovarian cancer cells. Hindawi 2019-10-31 /pmc/articles/PMC6875340/ /pubmed/31781333 http://dx.doi.org/10.1155/2019/3461251 Text en Copyright © 2019 Alessandro Salatino et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Salatino, Alessandro
Aversa, Ilenia
Battaglia, Anna Martina
Sacco, Alessandro
Di Vito, Anna
Santamaria, Gianluca
Chirillo, Roberta
Veltri, Pierangelo
Tradigo, Giuseppe
Di Cello, Annalisa
Venturella, Roberta
Biamonte, Flavia
Costanzo, Francesco
H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title_full H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title_fullStr H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title_full_unstemmed H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title_short H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS
title_sort h-ferritin affects cisplatin-induced cytotoxicity in ovarian cancer cells through the modulation of ros
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875340/
https://www.ncbi.nlm.nih.gov/pubmed/31781333
http://dx.doi.org/10.1155/2019/3461251
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