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Open AccessArticle

Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells

Department of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, Spain
Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Sevilla, Spain
Departamento de Cirugía General, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 41013 Sevilla, Spain
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain
Author to whom correspondence should be addressed.
Antioxidants 2019, 8(10), 501;
Received: 11 September 2019 / Revised: 11 October 2019 / Accepted: 21 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Thioredoxin Family Proteins)
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. View Full-Text
Keywords: hepatocarcinoma; thioredoxin; sorafenib; redox signaling; EMT hepatocarcinoma; thioredoxin; sorafenib; redox signaling; EMT
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López-Grueso, M.J.; González, R.; Muntané, J.; Bárcena, J.A.; Padilla, C.A. Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells. Antioxidants 2019, 8, 501.

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