title: Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Stefanovic
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Tutusaus
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Martinez-Nieto
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: de Gregorio
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Barbero-Camps
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.|Liver Unit, Hospital Clinic, CIBEREHD, Barcelona, Catalonia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.|Liver Unit, Hospital Clinic, CIBEREHD, Barcelona, Catalonia, Spain.|Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of The University of Southern California, Los Angeles, CA, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernandez-Checa
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; C001996:thermozymocidin
keywords: ceramide; chemotherapy; liver cancer; mitochondria; mouse model
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