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Carcinogenesis Advance Access published online on April 11, 2003
Carcinogenesis, doi:10.1093/carcin/bgg055
© 2003 by Oxford University Press
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© 2003 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Sphingolipids suppress preneoplastic rat hepatocytes in vitro and in vivo

Ilona Silins 1, Mariann Nordstrand 1, Johan Högberg 1, Ulla Stenius 1*

1 Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-17177 Stockholm, Sweden

* Corresponding author. E-mail: ulla.stenius{at}imm.ki.se.

Received 4 November 2002 ; revised 12 March 2003 ; accepted 17 March 2003

Abstract

Sphingolipids can modulate cell growth, differentiation and apoptosis. In the present investigation, selective death of hepatocytes localized in enzyme-altered foci (EAF hepatocytes) was shown to be induced by sphingolipids in vitro. 20 µM sphingosine, caused rapid cell death predominantly of EAF hepatocytes in vitro. During 4 hours of such exposure, cytochrome c was released from mitochondria into the cytoplasm and the number of cells demonstrating cleaved caspase-9 activity increased. The selective sensitivity of EAF cells to sphingolipid-induced death was attenuated by tumor necrosis factor-{alpha}. In previous studies we have demonstrated that EAF hepatocytes are resistant to Fas-mediated apoptosis, a resistance shown here to be reversed by low concentrations of sphingosine. Immunohistological staining revealed higher levels of glucosylated ceramide in EAF than in the surrounding tissue. Furthermore, an inhibitor of glucosylation enhanced the toxicity of ceramide towards EAF cells. TLC analysis suggested low levels of sphingosine in preneoplastic lesions. In in vivo experiments EAF-bearing rats were fed a diet supplemented with 0.1% sphingomyelin for two weeks. Sphingolipid feeding reduced the number of EAF and EAF area in the liver by 40-50% as compared to rats fed a control diet. These studies indicate that the turnover of sphingolipids in preneoplastic EAF hepatocytes is altered. This alteration may explain not only the increased sensitivity of EAF cells towards sphingolipid-induced cell death, but also the resistance of these hepatocytes to cell death involving sphingolipids as second messengers. Furthermore, sphingomyelin in the diet may prevent EAF development. It is suggested that the altered turnover of sphingolipids might be a target for chemoprevention of hepatocellular carcinoma.


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