Resminostat induces changes in epithelial plasticity of hepatocellular carcinoma cells and sensitizes them to sorafenib-induced apoptosis
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Jitka Soukupova1, Esther Bertran1, Irene Peñuelas-Haro1, Uxue Urdiroz-Urricelqui1,2, Matthias Borgman3, Hella Kohlhof3,4 and Isabel Fabregat1,2
1“TGF-β and cancer” group, Oncobell Program. Bellvitge Biomedical Research Institute, (IDIBELL), L´Hospitalet, Barcelona, Spain
2Department of Physiological Sciences, Faculty of Medicine and Health Sciences. University of Barcelona (UB), L´Hospitalet, Barcelona, Spain
34SC AG, Planegg-Martinsried, Germany
4Immunic AG, Planegg-Martinsried, Germany
Isabel Fabregat, email: firstname.lastname@example.org
Keywords: HDAC inhibitors; HCC; EMT; resminostat; sorafenib
Received: March 29, 2017 Accepted: November 17, 2017 Published: November 30, 2017
Resminostat, a novel class I, IIb, and IV histone deacetylase inhibitor, was studied in advanced hepatocellular carcinoma (HCC) patients after relapse to sorafenib (SHELTER study). In this phase I/II clinical trial, combination of sorafenib and resminostat was safe and showed early signs of efficacy. However, the molecular mechanisms behind this synergism have not been explored yet. In this work, we aimed to analyze whether resminostat regulates epithelial-mesenchymal and stemness phenotype as a mechanism of sensitization to sorafenib. Three HCC cell lines with differences in their epithelial/mesenchymal characteristics were treated with resminostat and sorafenib alone, or in combination. Resminostat prevented growth and induced cell death in the HCC cells, in a time and dose dependent manner. A collaborative effect between resminostat and sorafenib was detected in the mesenchymal HCC cells, which were insensitive to sorafenib-induced apoptosis. Expression of mesenchymal-related genes was decreased in resminostat-treated HCC cells, concomitant with an increase in epithelial-related gene expression, organized tight junctions and reduced invasive growth. Moreover, resminostat down-regulated CD44 expression, coincident with decreased capacity to form colonies at low cell density. Conclusion: Resminostat shifts mesenchymal cells towards a more epithelial phenotype, lower invasive and stemness properties, which may contribute to the sensitization to sorafenib-induced apoptosis.
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