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Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects. However, recent reports suggest that sphingolipid metabolism in ceramide-resistant cancer cells favors the conversion of exogenous ceramides to prosurvival sphingolipids, conferring ceramide resistance to cancer cells. However, the mechanism underlying ceramide resistance remains unclear. We previously demonstrated that diTFPP, a novel phenoxyphenol compound, enhances the anti-HCC effect of C₂-ceramide. Here, we further clarified that treatment with C₂-ceramide alone increases the protein level of CERS2, which modulates sphingolipid metabolism to favor the conversion of C₂-ceramide to prosurvival sphingolipids in HCC cells, thus activating the unfolded protein response (UPR), which further initiates autophagy and the reversible senescence-like phenotype (SLP), ultimately contributing to C₂-ceramide resistance in these cells. However, cotreatment with diTFPP and ceramide downregulated the protein level of CERS2 and increased oxidative and endoplasmic reticulum (ER) stress. Furthermore, insufficient LAMP2 glycosylation induced by diTFPP/ceramide cotreatment may cause the failure of autophagosome–lysosome fusion, eventually lowering the threshold for triggering cell death in response to C₂-ceramide. Our study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics. Full article

Hepatocellular carcinoma (HCC) is a severe disease that accounts for 80% of liver cancers. Chemotherapy is the primary therapeutic strategy for patients who cannot be treated with surgery or who have late-stage HCC. C₂-ceramide is an effective reagent that has been found to inhibit the growth of many cancer types. The metabolism of C₂-ceramide plays a vital role in the regulation of cell death/cell survival. The phenoxyphenol compound 4-{2,3,5,6-tetrafluoro-4-[2,3,5,6-tetrafluoro-4-(4-hydroxyphenoxy)phenyl]phenoxy}phenol (diTFPP) was found to have a synergistic effect with C₂-ceramide, resulting in considerable cell death in the HA22T HCC cell line. diTFPP/C₂-ceramide cotreatment induced a two- to threefold increase in cell death compared to that with C2-ceramide alone and induced pyknosis. Annexin V/7-aminoactinomycin D (7AAD) double staining and Western blotting indicated that apoptosis was involved in diTFPP/C₂-ceramide cotreatment-mediated cell death. We next analyzed transcriptome alterations in diTFPP/C₂-ceramide-cotreated HA22T cells with next-generation sequencing (NGS). The data indicated that diTFPP treatment disrupted sphingolipid metabolism, inhibited cell cycle-associated gene expression, and induced autophagy and reactive oxygen species (ROS)-responsive changes in gene expression. Additionally, we assessed the activation of autophagy with acridine orange (AO) staining and observed alterations in the expression of the autophagic proteins LC3B-II and Beclin-1, which indicated autophagy activation after diTFPP/C₂-ceramide cotreatment. Elevated levels of ROS were also reported in diTFPP/C₂-ceramide-treated cells, and the expression of the ROS-associated proteins SOD1, SOD2, and catalase was upregulated after diTFPP/C₂-ceramide treatment. This study revealed the potential regulatory mechanism of the novel compound diTFPP in sphingolipid metabolism by showing that it disrupts ceramide metabolism and apoptotic sphingolipid accumulation. Full article