Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells
Sorafenib is the first-line recommended therapy for patients with advanced hepatocarcinoma (HCC) in de-differentiation stage (presenting epithelial−mesenchymal transition, EMT). We studied the role of the thioredoxin system (Trx1/TrxR1) in the sensitivity or resistance of HCC cells to the...
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doaj-0cf8711fe7b44be0b78f5f08b99b99e02020-11-25T01:26:12ZengMDPI AGAntioxidants2076-39212019-10-0181050110.3390/antiox8100501antiox8100501Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma CellsMaría José López-Grueso0Raúl González1Jordi Muntané2José Antonio Bárcena3C. Alicia Padilla4Department of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, SpainInstitute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Sevilla, SpainInstitute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Sevilla, SpainDepartment of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, SpainDepartment of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, SpainSorafenib is the first-line recommended therapy for patients with advanced hepatocarcinoma (HCC) in de-differentiation stage (presenting epithelial−mesenchymal transition, EMT). We studied the role of the thioredoxin system (Trx1/TrxR1) in the sensitivity or resistance of HCC cells to the treatment with Sorafenib. As a model, we used a set of three established HCC cell lines with different degrees of de-differentiation as occurs in metastasis. By quantitative proteomics, we found that the expression levels of Trx1 and TrxR1 followed the same trend as canonical EMT markers in these cell lines. Treatment with Sorafenib induced thiol redox reductive changes in critical elements of oncogenic pathways in all three cell lines but induced drastic proteome reprograming only in HCC cell lines of intermediate stage. Trx1 downregulation counteracted the thiol reductive effect of Sorafenib on Signal Transducer and Activator of Transcription 3 (STAT3) but not on Mitogen-Activated Protein Kinase (MAPK) or Protein Kinase B (Akt) and transformed advanced HCC cells into Sorafenib-sensitive cells. Ten targets of the combined Sorafenib−siRNATrx1 treatment were identified that showed a gradually changing expression trend in parallel to changes in the expression of canonical EMT markers, likely as a result of the activation of Hippo signaling. These findings support the idea that a combination of Sorafenib with thioredoxin inhibitors should be taken into account in the design of therapies against advanced HCC.https://www.mdpi.com/2076-3921/8/10/501hepatocarcinomathioredoxinsorafenibredox signalingemt |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
María José López-Grueso Raúl González Jordi Muntané José Antonio Bárcena C. Alicia Padilla |
spellingShingle |
María José López-Grueso Raúl González Jordi Muntané José Antonio Bárcena C. Alicia Padilla Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells Antioxidants hepatocarcinoma thioredoxin sorafenib redox signaling emt |
author_facet |
María José López-Grueso Raúl González Jordi Muntané José Antonio Bárcena C. Alicia Padilla |
author_sort |
María José López-Grueso |
title |
Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells |
title_short |
Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells |
title_full |
Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells |
title_fullStr |
Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells |
title_full_unstemmed |
Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells |
title_sort |
thioredoxin downregulation enhances sorafenib effects in hepatocarcinoma cells |
publisher |
MDPI AG |
series |
Antioxidants |
issn |
2076-3921 |
publishDate |
2019-10-01 |
description |
Sorafenib is the first-line recommended therapy for patients with advanced hepatocarcinoma (HCC) in de-differentiation stage (presenting epithelial−mesenchymal transition, EMT). We studied the role of the thioredoxin system (Trx1/TrxR1) in the sensitivity or resistance of HCC cells to the treatment with Sorafenib. As a model, we used a set of three established HCC cell lines with different degrees of de-differentiation as occurs in metastasis. By quantitative proteomics, we found that the expression levels of Trx1 and TrxR1 followed the same trend as canonical EMT markers in these cell lines. Treatment with Sorafenib induced thiol redox reductive changes in critical elements of oncogenic pathways in all three cell lines but induced drastic proteome reprograming only in HCC cell lines of intermediate stage. Trx1 downregulation counteracted the thiol reductive effect of Sorafenib on Signal Transducer and Activator of Transcription 3 (STAT3) but not on Mitogen-Activated Protein Kinase (MAPK) or Protein Kinase B (Akt) and transformed advanced HCC cells into Sorafenib-sensitive cells. Ten targets of the combined Sorafenib−siRNATrx1 treatment were identified that showed a gradually changing expression trend in parallel to changes in the expression of canonical EMT markers, likely as a result of the activation of Hippo signaling. These findings support the idea that a combination of Sorafenib with thioredoxin inhibitors should be taken into account in the design of therapies against advanced HCC. |
topic |
hepatocarcinoma thioredoxin sorafenib redox signaling emt |
url |
https://www.mdpi.com/2076-3921/8/10/501 |
work_keys_str_mv |
AT mariajoselopezgrueso thioredoxindownregulationenhancessorafenibeffectsinhepatocarcinomacells AT raulgonzalez thioredoxindownregulationenhancessorafenibeffectsinhepatocarcinomacells AT jordimuntane thioredoxindownregulationenhancessorafenibeffectsinhepatocarcinomacells AT joseantoniobarcena thioredoxindownregulationenhancessorafenibeffectsinhepatocarcinomacells AT caliciapadilla thioredoxindownregulationenhancessorafenibeffectsinhepatocarcinomacells |
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