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Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma

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....

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Autores principales: Stefanovic, Milica, Tutusaus, Anna, Martinez-Nieto, Guillermo A., Bárcena, Cristina, de Gregorio, Estefania, Moutinho, Catia, Barbero-Camps, Elisabet, Villanueva, Alberto, Colell, Anna, Marí, Montserrat, García-Ruiz, Carmen, Fernandez-Checa, Jose C., Morales, Albert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884990/
https://www.ncbi.nlm.nih.gov/pubmed/26811497
http://dx.doi.org/10.18632/oncotarget.6982
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author Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Bárcena, Cristina
de Gregorio, Estefania
Moutinho, Catia
Barbero-Camps, Elisabet
Villanueva, Alberto
Colell, Anna
Marí, Montserrat
García-Ruiz, Carmen
Fernandez-Checa, Jose C.
Morales, Albert
author_facet Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Bárcena, Cristina
de Gregorio, Estefania
Moutinho, Catia
Barbero-Camps, Elisabet
Villanueva, Alberto
Colell, Anna
Marí, Montserrat
García-Ruiz, Carmen
Fernandez-Checa, Jose C.
Morales, Albert
author_sort Stefanovic, Milica
collection PubMed
description 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.
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spelling pubmed-48849902016-06-17 Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma Stefanovic, Milica Tutusaus, Anna Martinez-Nieto, Guillermo A. Bárcena, Cristina de Gregorio, Estefania Moutinho, Catia Barbero-Camps, Elisabet Villanueva, Alberto Colell, Anna Marí, Montserrat García-Ruiz, Carmen Fernandez-Checa, Jose C. Morales, Albert Oncotarget Research Paper 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. Impact Journals LLC 2016-01-22 /pmc/articles/PMC4884990/ /pubmed/26811497 http://dx.doi.org/10.18632/oncotarget.6982 Text en Copyright: © 2016 Stefanovic et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Bárcena, Cristina
de Gregorio, Estefania
Moutinho, Catia
Barbero-Camps, Elisabet
Villanueva, Alberto
Colell, Anna
Marí, Montserrat
García-Ruiz, Carmen
Fernandez-Checa, Jose C.
Morales, Albert
Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title_full Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title_fullStr Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title_full_unstemmed Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title_short Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
title_sort targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884990/
https://www.ncbi.nlm.nih.gov/pubmed/26811497
http://dx.doi.org/10.18632/oncotarget.6982
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