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.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver cancer and the end stage of chronic liver disease [1]
Recent data has shown the efficacy of combining sorafenib with recombinant acid sphingomyelinase, a ceramidegenerating enzyme, in experimental liver cancer [14], or with nanoliposomal ceramide in melanoma or breast cancer [15]. These findings have proposed a role for sphingolipids in sorafenib toxicity [16], but a detailed analysis of ceramide metabolism in vitro and in vivo HCC models after sorafenib treatment has not been previously reported
Fig. 1), we found that overnight sorafenib exposure increased expression of genes responsible for ceramide production (Table 1) by sphingomyelin hydrolysis or de novo synthesis
Summary
Hepatocellular carcinoma (HCC) is the most common liver cancer and the end stage of chronic liver disease [1]. HCC is often diagnosed in an advanced stage characterized by resistance to current therapy, when curative strategies are no longer applicable. The establishment of the multikinase inhibitor sorafenib as the standard of care has opened a window of hope for HCC patients with very poor prognosis [3]. This promising systemic treatment has limited survival www.impactjournals.com/oncotarget Sorafenib (μM) ASMase 1.00±0.32 2.05±0.66 * 2.39±0.22 * NSMase 1.00±0.10 0.90±0.20 1.10±0.20 ACDase
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