C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells.
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.
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Shanshan
S
Jiang
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Qian
Q
Wang
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Meiqing
M
Feng
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Jiyang
J
Li
Shanghai Institute For Food And Drug Control, Shanghai, China.
Zhongbin
Z
Guan
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Duopeng
D
An
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Mengxue
M
Dong
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Yuzhe
Y
Peng
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Kudelaidi
K
Kuerban
Department of Biosynthesis and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China. yelil@fudan.edu.cn.
Li
L
Ye
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077157:Sorafenib; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; C064769:N-acetylsphingosine; C546842:MTOR protein, human
Apoptosis; C2-ceramide; EMT; HCC; Orafenib; PI3K/AKT/mTOR