Related Experiment Video
Updated: Mar 26, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular
Milica Stefanovic1, Anna Tutusaus1, Guillermo A Martinez-Nieto1
1Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalonia, Spain.
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.
Insights
Targeting glucosylceramide synthase (GCS) overcomes sorafenib resistance in hepatocellular carcinoma (HCC). Inhibiting GCS restores sorafenib sensitivity, offering a new strategy for HCC treatment by sensitizing mitochondria.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Sorafenib is a tyrosine kinase inhibitor used for hepatocellular carcinoma (HCC).
- Evasive mechanisms, including sphingolipid dysregulation and ceramide metabolism, contribute to sorafenib resistance in cancer.
- The specific role of ceramide-modifying enzymes in sorafenib resistance in HCC remains unclear.
Purpose of the Study:
- To investigate the role of ceramide-modifying enzymes, specifically glucosylceramide synthase (GCS), in sorafenib resistance in HCC.
- To evaluate GCS inhibition as a potential strategy to enhance sorafenib efficacy in HCC.
Main Methods:
- Assessed GCS expression in hepatoma cells (HepG2, Hep3B) and sorafenib-resistant HCC cell lines during sorafenib treatment.
- Utilized GCS silencing and pharmacological GCS inhibition to sensitize cells to sorafenib.
- Investigated the effects of GCS inhibition on mitochondrial pathways (cytochrome c release, ATP depletion) and cell death.
- Evaluated GCS inhibition in combination with sorafenib in a xenograft mouse model of HCC.
Main Results:
- GCS was upregulated in hepatoma cells and sorafenib-resistant HCC cell lines upon sorafenib treatment.
- GCS silencing or inhibition sensitized HCC cells to sorafenib, inducing mitochondrial cell death.
- Genetic overexpression of GCS conferred resistance to sorafenib.
- Combined GCS inhibition and sorafenib treatment improved drug efficacy in a mouse model, restoring sensitivity in resistant tumors.
Conclusions:
- GCS induction is a key mechanism driving sorafenib resistance in HCC.
- Targeting GCS represents a novel therapeutic strategy to potentiate sorafenib efficacy in HCC management.
- The mitochondria are a critical subcellular target for enhancing sorafenib therapy in HCC.
