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Título: | Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma |
Autor: | Stefanovic, Milica CSIC; Tutusaus, Anna CSIC ORCID; Martínez-Nieto, Guillermo A. CSIC; Bárcena, Cristina CSIC ORCID; Gregorio, Estefanía de CSIC; Barbero-Camps, Elisabet CSIC; Colell Riera, Anna CSIC ORCID; Marí, Montserrat CSIC ORCID ; García-Ruiz, Carmen CSIC ORCID ; Fernández-Checa, José C. CSIC ORCID; Morales, Albert CSIC ORCID | Palabras clave: | Mitochondria Liver cancer Chemotherapy Ceramide Mouse model |
Fecha de publicación: | 22-ene-2016 | Editor: | Impact Journals | Citación: | Oncotarget 7: 8253-8267 (2016) | Resumen: | Evasive 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. | Versión del editor: | https://doi.org/10.18632/oncotarget.6982 | URI: | http://hdl.handle.net/10261/148812 | DOI: | 10.18632/oncotarget.6982 | Identificadores: | doi: 10.18632/oncotarget.6982 issn: 1949-2553 |
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Targeting glucosylceramide-Stefanovic.pdf | 8,87 MB | Adobe PDF | Visualizar/Abrir |
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