English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/148812
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:


Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma

AuthorsStefanovic, Milica ; Tutusaus, Anna; Martínez-Nieto, Guillermo A. ; Bárcena, Cristina ; Gregorio, Estefanía de; Barbero-Camps, Elisabet ; Colell Riera, Anna ; Marí, Montserrat ; García-Ruiz, Carmen ; Fernández-Checa, José C. ; Morales, Albert
Liver cancer
Mouse model
Issue Date22-Jan-2016
PublisherImpact Journals
CitationOncotarget 7: 8253-8267 (2016)
AbstractEvasive mechanisms triggered by the tyrosine kinase inhibitor sorafenib reduce its efficacy in hepatocellular carcinoma (HCC) treatment. Drug-resistant cancer cells frequently exhibit sphingolipid dysregulation, reducing chemotherapeutic cytotoxicity via the induction of ceramide-degrading enzymes. However, the role of ceramide in sorafenib therapy and resistance in HCC has not been clearly established. Our data reveals that ceramide-modifying enzymes, particularly glucosylceramide synthase (GCS), are upregulated during sorafenib treatment in hepatoma cells (HepG2 and Hep3B), and more importantly, in sorafenib-resistant cell lines. GCS silencing or pharmacological GCS inhibition sensitized hepatoma cells to sorafenib exposure. GCS inhibition, combined with sorafenib, triggered cytochrome c release and ATP depletion in sorafenib-treated hepatoma cells, leading to mitochondrial cell death after energetic collapse. Conversely, genetic GCS overexpression increased sorafenib resistance. Of interest, GCS inhibition improved sorafenib effectiveness in a xenograft mouse model, recovering drug sensitivity of sorafenib-resistant tumors in mice. In conclusion, our results reveal GCS induction as a mechanism of sorafenib resistance, suggesting that GCS targeting may be a novel strategy to increase sorafenib efficacy in HCC management, and point to target the mitochondria as the subcellular location where sorafenib therapy could be potentiated.
Publisher version (URL)https://doi.org/10.18632/oncotarget.6982
Identifiersdoi: 10.18632/oncotarget.6982
issn: 1949-2553
Appears in Collections:(IIBB) Artículos
Files in This Item:
File Description SizeFormat 
Targeting glucosylceramide-Stefanovic.pdf8,87 MBAdobe PDFThumbnail
Show full item record
Review this work

Related articles:

WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.