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

  • Applied genetics and molecular biotechnology
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Abstract

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.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81572979); National Key Basic Research Program of China (2015CB931800); and School of Pharmacy, Fudan University and The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China.

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  1. Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China

    Shanshan Jiang, Qian Wang, Meiqing Feng, Jiyang Li, Duopeng An, Mengxue Dong, Yuzhe Peng, Kudelaidi Kuerban & Li Ye

  2. Shanghai Institute For Food And Drug Control, Shanghai, China

    Zhongbin Guan

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  1. Shanshan Jiang
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  2. Qian Wang
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Jiang, S., Wang, Q., Feng, M. et al. C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells. Appl Microbiol Biotechnol 101, 1535–1546 (2017). https://doi.org/10.1007/s00253-016-7930-9

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