Research Papers:

Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma

Milica Stefanovic, Anna Tutusaus, Guillermo A. Martinez-Nieto, Cristina Bárcena, Estefania de Gregorio, Catia Moutinho, Elisabet Barbero-Camps, Alberto Villanueva, Anna Colell, Montserrat Marí, Carmen García-Ruiz, Jose C. Fernandez-Checa and Albert Morales _

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Oncotarget. 2016; 7:8253-8267. https://doi.org/10.18632/oncotarget.6982

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Milica Stefanovic1, Anna Tutusaus1, Guillermo A. Martinez-Nieto1, Cristina Bárcena1, Estefania de Gregorio1, Catia Moutinho2, Elisabet Barbero-Camps1, Alberto Villanueva3, Anna Colell1, Montserrat Marí1, Carmen García-Ruiz1,4, Jose C. Fernandez-Checa1,4,5, Albert Morales1

1Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain

2Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain

3Translational Research Laboratory, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain

4Liver Unit, Hospital Clinic, CIBEREHD, Barcelona, Catalonia, Spain

5Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Correspondence to:

Albert Morales, e-mail: [email protected]

Jose C. Fernandez-Checa, e-mail: [email protected]

Keywords: liver cancer, chemotherapy, mitochondria, ceramide, mouse model

Received: July 27, 2015     Accepted: January 13, 2016     Published: January 22, 2016


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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