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Carcinogenesis Advance Access published online on July 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi187
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 3, 2005
Revised June 23, 2005
Accepted July 15, 2005

CANCER BIOLOGY

A role for caspase-8 and c-FLIPL in proliferation and cell cycle progression of primary hepatocytes

David Gilot 1*, Anne-Laure Serandour 2, Guennady P. Ilyin 2, Dominique Lagadic-Gossmann 1, Pascal Loyer 2, Anne Corlu 2, Alexandre Coutant 2, Georges Baffet 2, Marcus E. Peter 3, Olivier Fardel 1, and Christiane Guguen-Guillouzo 2

1 INSERM U620, Rennes, F-35043 France; Université de Rennes 1, Rennes, F-35043 France
2 INSERM U522, Hôpital Pontchaillou, Rennes, F-35033 France
3 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA

* To whom correspondence should be addressed.
David Gilot, E-mail: david.gilot{at}rennes.inserm.fr


  Abstract

Growth factors are known to favor both proliferation and survival of hepatocytes. Here, we investigated if c-FLIPL (cellular FLICE-inhibitory protein, long isoform) could be involved in epidermal growth factor (EGF)-stimulated proliferation of rat hepatocytes since c-FLIPL regulates both cell proliferation and procaspase-8 maturation. Treatment with MEK inhibitors prevented induction of c-FLIPL by EGF along with total inhibition of DNA replication. However, EGF failed to inhibit processing of procaspase-8 in the presence of EGF suggesting that c-FLIPL does not play its canonical anti-apoptotic role in this model. Down-regulation of c-FLIP expression using siRNA oligonucleotides strongly reduced DNA replication but did not result in enhanced apoptosis. Moreover, intermediate cleavage products of c-FLIPL and caspase-8 were found in EGF-treated hepatocytes in absence of caspase-3 maturation and cell death. To determine whether the Fas/FADD/caspase-8/c-FLIPL complex was required for this activity, Fas, procaspase-8 and FADD expression or function was inhibited using siRNA or constructs encoding dominant negative mutant proteins. Inhibition of any of these components of the Fas/FADD/caspase-8 pathway decreased DNA replication suggesting a function of these proteins in cell cycle arrest. Similar results were obtained when the IETD-like caspase activity detectable in EGF-treated hepatocytes was inhibited by the pancaspase inhibitor, z-ASP. Finally, we demonstrated coimmunoprecipitation between EGFR and Fas within 15 minutes following EGF stimulation. In conclusion, our results indicate that the Fas/FADD/c-FLIPL/caspase-8 pathway positively controls the G1/S transition in EGF-stimulated hepatocytes. Our data provide new insights into the mechanisms by which apoptotic proteins participate to mitogenic signals during the G1 phase.


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