C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells

• Published in: Applied microbiology and biotechnology 2017-02, Vol.101 (4), p.1535-1546
• Main Authors: Jiang, Shanshan, Wang, Qian, Feng, Meiqing, Li, Jiyang, Guan, Zhongbin, An, Duopeng, Dong, Mengxue, Peng, Yuzhe, Kuerban, Kudelaidi, Ye, Li
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Apoptosis - drug effects; Applied Genetics and Molecular Biotechnology; Biomedical and Life Sciences; Biotechnology; Cancer therapies; Cancer treatment; Carcinoma, Hepatocellular - metabolism; Cell adhesion & migration; Cell cycle; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; Cellular biology; Combination therapy; Cytochrome; Cytochrome c; Drug therapy; Flow Cytometry; Growth factors; Humans; Kinases; Life Sciences; Liver cancer; Medical research; Microbial Genetics and Genomics; Microbiology; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Pathogenesis; Phenylurea Compounds - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Prescription drugs; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Studies; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-016-7930-9

Sorafenib as an effective multikinase inhibitor has been approved for the clinical treatment against advanced hepatocellular carcinoma (HCC). HCC treatment requires usually combined therapy because of its complex pathogenesis. Ceramide has been confirmed to induce remarkable apoptosis in human tumor cells and has attracted increasing attention in investigations on combination therapy. In this paper, the anti-HCC effect of sorafenib combined with C2-ceramide was investigated on cell vitality, apoptosis, and migration, and the underlying mechanism was examined using flow cytometry and western blot. Bel7402 cells coincubated with sorafenib and C2-ceramide exhibited lower cell vitality and more irregular cellular morphology and cell cycle arrest. Sorafenib plus C2-ceramide stimulated significantly the production of reactive oxygen species (ROS) and mitochondrial depolarization, which promoted caspases-dependent cell apoptosis as illustrated by related protein expression including caspase 3, caspase 9, Bax, Bcl-2, and cytochrome c. Combination treatment of sorafenib and C2-ceramide inhibited obviously cell growth and proliferation via PI3K/AKT/mTOR and Erk signaling pathways. Furthermore, the combination treatment was proved to inhibit cell migration and epithelial-mesenchymal transition (EMT). These findings indicated that the combination of C2-ceramide and sorafenib provided synergistic inhibitory effects on HCC cells.