thermozymocidin and Carcinoma--Hepatocellular

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.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Ceramides; Drug Resistance, Neoplasm; Fatty Acids, Monounsaturated; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glucosyltransferases; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Liver Neoplasms, Experimental; Male; Mice; Mice, Nude; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sorafenib; Tumor Cells, Cultured; Xenograft Model Antitumor Assays