Failure of lamivudine to reverse hepatitis B virus-associated changes in ERK, Akt and cell cycle regulatory proteins.
BACKGROUND
Chronic infection with hepatitis B virus (HBV) is a major factor associated with the development of hepatocellular carcinoma, but the mechanism by which this occurs is unknown. Treatment of chronic hepatitis B with lamivudine results in virological suppression and histological improvement; however, the role of lamivudine in preventing the development of hepatocellular carcinoma is less well defined. We recently reported that replication of HBV in a cell-culture system was associated with the upregulation of pERK, pAkt, pc-Myc, nuclear cyclin B1, p21(cip1) and p53 together with G2 cell cycle arrest.


METHODS
In order to determine whether lamivudine is able to reverse the HBV-induced changes on signal transduction and cell cycle, we infected Huh7 cells with a recombinant adeno-HBV virus in the presence of 0-50 microM of lamivudine. Signal transduction and cell cycle regulatory proteins were analysed by western immunoblot.


RESULTS
Although lamivudine was able to inhibit HBV replication, it failed to reverse the changes on ERK and Akt phosphorylation. Correspondingly, levels of phospho-GSK3beta and p21(cp1/waf1) were increased, as were cyclin D1, cyclin B1, p53 and pc-Myc.


CONCLUSIONS
Lamivudine was ineffective in reversing the HBV-induced changes in signal transduction pathways and cell cycle regulatory proteins, indicating that the HBV-infected cells remained primed for oncogenic transformation despite viral suppression.
Chin
Ruth
R
Department of Medicine, CCREID, Royal Melbourne Hospital, University of Melbourne, Australia.
Earnest-Silveira
Linda
L
Koeberlein
Bernd
B
Franz
Susanne
S
Zentgraf
Hanswalter
H
Bowden
Scott
S
Bock
C-Thomas
CT
Torresi
Joseph
J
D000998:Antiviral Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006515:Hepatitis B virus / Q000201:enzymology / Q000472:pathogenicity*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000998:Antiviral Agents; D018797:Cell Cycle Proteins; D019259:Lamivudine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases