Tumor Biology

, Volume 36, Issue 8, pp 5763–5771 | Cite as

Ceramide production mediates cinobufotalin-induced growth inhibition and apoptosis in cultured hepatocellular carcinoma cells

Research Article

Abstract

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.

Keywords

Hepatocellular carcinoma Cinobufotalin Apoptosis SphK1 and ceramide 

Abbreviations

CerS-1

Ceramide synthase 1

HCC

Hepatocellular carcinoma

SphK1

Sphingosine kinase 1

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Interventional RadiologyThe Second Affiliated Hospital of Soochow University, Soochow UniversitySuzhouChina
  2. 2.Department of Burn SurgeryThe Linyi People’s HospitalLinyiChina
  3. 3.Department of RadiotherapyHubei Cancer HospitalWuhanChina
  4. 4.Department of Hand and Foot SurgeryThe Second Affiliated Hospital of Soochow University, Soochow UniversitySuzhouChina

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