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

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Tumor Biology

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.

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Abbreviations

CerS-1:

Ceramide synthase 1

HCC:

Hepatocellular carcinoma

SphK1:

Sphingosine kinase 1

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Acknowledgments

This work was supported by the National Natural Science Foundation.

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Authors and Affiliations

  1. Department of Interventional Radiology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215001, China

    Long Cheng, Xin-shi Gu, Yong Jin & Xu-ming Bai

  2. Department of Burn Surgery, The Linyi People’s Hospital, Linyi, 276000, China

    Yuan-zheng Chen

  3. Department of Radiotherapy, Hubei Cancer Hospital, Wuhan, 430000, China

    Yi Peng

  4. Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215001, China

    Nan Yi

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  1. Long Cheng
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  2. Yuan-zheng Chen
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Correspondence to Yong Jin or Xu-ming Bai.

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Long Cheng and Yuan-zheng Chen are co-first authors.

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Cheng, L., Chen, Yz., Peng, Y. et al. Ceramide production mediates cinobufotalin-induced growth inhibition and apoptosis in cultured hepatocellular carcinoma cells. Tumor Biol. 36, 5763–5771 (2015). https://doi.org/10.1007/s13277-015-3245-1

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  • DOI: https://doi.org/10.1007/s13277-015-3245-1

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