Ceramide production mediates cinobufotalin-induced growth inhibition and apoptosis in cultured hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal neoplasm with poor prognosis. The aim of this study is to investigate the anticancer activity of cinobufotalin, a bufadienolide isolated from toad venom, in cultured HCC cells, and to study the underlying mechanisms. We found that cinobufotalin (at nmol/L) significantly inhibited HCC cell growth and survival while inducing considerable cell apoptosis. Further, cinobufotalin inhibited sphingosine kinase 1 (SphK1) activity and induced pro-apoptotic ceramide production. Ceramide synthase-1 small hairpin RNA (shRNA)-depletion inhibited cinobufotalin-induced ceramide production and HCC cell apoptosis. On the other hand, the glucosylceramide synthase (GCS) inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) facilitated cinobufotalin-induced ceramide production and cell apoptosis. SphK1 inhibitor II (SKI-II), similar to cinobufotalin, increased cellular ceramide level and promoted HCC cell apoptosis. Finally, we observed that cinobufotalin inactivated Akt-S6K1 signaling in HepG2 cells, which was again inhibited by ceramide synthase-1 shRNA-depletion. In conclusion, the results of this study suggest that cinobufotalin induces growth inhibition and apoptosis in cultured HCC cells through ceramide production. Cinobufotalin may be investigated as a novel anti-HCC agent.
Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215001, China.
Long
L
Cheng
Yuan-Zheng
YZ
Chen
Yi
Y
Peng
Nan
N
Yi
Xin-Shi
XS
Gu
Yong
Y
Jin
Xu-Ming
XM
Bai
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage; D051049:Sphingosine N-Acyltransferase / Q000037:antagonists & inhibitors
D048868:Adaptor Proteins, Signal Transducing; D002018:Bufanolides; D002518:Ceramides; D009025:Morpholines; C466999:SPHKAP protein, human; C033110:RV 538; D051049:Sphingosine N-Acyltransferase; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; C063451:cinobufotalin