Failure of Lamivudine to Reverse Hepatitis B Virus-Associated Changes in ERK, Akt and Cell Cycle Regulatory Proteins

Abstract

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, p21cip1 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 μM 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-GSK3β and p21cip1/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.

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

“…Despite the absence of literature references on the regulatory effects of doravirine and cabotegravir on the cell cycle and cell death, a study conducted on a hepatocellular carcinoma cell line indicated that lamivudine was ineffective in reversing HBV-induced changes in cell cycle regulatory proteins [64]. Conversely, other studies have reported the pro-apoptotic effects of lamivudine in various cancer cell types, including hepatocellular carcinoma Huh-7 and Hep-G2 cell lines [65], as well as in breast [66], lung [67], and esophageal [68] cancer cells.…”