Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed chinese hamster ovary cells

Abstract

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma. Several lines of evidence suggest that the core protein of HCV may play a role in the development of this cancer. The authors examined regulation of the cell cycle in stable cell lines derived from Chinese hamster ovary (CHO-K1) cells that constitutively expressed one or more of the structural proteins of HCV. In media containing low concentrations of serum (serum starvation), cell lines expressing the core protein showed a significantly lower population of viable cells than noncore-expressing cells. The low viability of the core-expressing cells was a result of the increased population of cells undergoing apoptosis. Interestingly, the cell cycle analysis revealed that the arresting function at G(0) was impaired, and the cell cycle was accelerated in core-expressing cell lines even under serum starvation. Thus, the HCV core protein sensitizes the apoptosis to serum starvation, although it promotes the cell cycle in CHO-K1 cells. To explain these findings, the authors examined the expression of revival apoptosis and cell-cycle-related genes. Expression of the c-myc genes was significantly induced in core-expressing cells in response to serum starvation. Other apoptosis-inducing genes downstream of c-myc, p53, p21WAF1/CIP1 and Bax were significantly highly induced, although there was no induction of Bcl-2, which prevents apoptosis in core-expressing cells. Thus, the HCV core protein induced apoptosis and impaired the regulation of the cell cycle by activating c-myc expression, whereas the p53 and Bax pathways play a role in the induction of apoptosis.

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

“…HCV core has been described as being associated with lymphotoxin-b receptor, TNF-receptor 1, apolipoprotein AII, hnRNP and a bZIP transcription factor (Barba et al, 1997;Chen et al, 1997;Hsieh et al, 1998;Sabile et al, 1999). Evidence exists that HCV core may have an e ect upon cell transformation (Jin et al, 2000) and apoptosis (Marusawa et al, 1999;Ray et al, 1996Ray et al, , 1998Ruggieri et al, 1997); however, the biological consequences of core ectopic expression depend on the levels of expression achieved, the cell type utilized and the cellular environment (Honda et al, 2000;Zhu et al, 1998).…”

Steatosis and liver cell apoptosis in chronic hepatitis C: A mechanism for increased liver injury

“…In different experimental conditions, the HCV core protein has been reported either to sensitize cells to death receptor-mediated apoptosis or to exert inhibitory effects through the activation of nuclear factor (NF)-B and induction of antiapoptotic gene products, including Bcl-2 and Bcl-x L . [15][16][17][18] It has not been determined whether steatosis or host factors such as BMI influence the apoptotic process in chronic hepatitis C. Interestingly, hepatocyte apoptosis recently was shown to be a prominent feature of nonalcoholic fatty liver disease. 19 In that study, a positive correlation was observed between hepatocyte apoptosis and both hepatic inflammatory activity and fibrosis, implicating a role for the apoptotic process in the progression of fatty liver disease.…”

Hepatitis C Virus Core Functions as a Suppressor of Cyclin-dependent Kinase-activating Kinase and Impairs Cell Cycle Progression

“…It has been reported that the HCV core binds to both p53 and p21 CIP1 (21,22) and impairs the cell cycle regulation in association with the increased expression of p21 CIP1 (22,35). As for the p53 status in the CL2 cells used for this study, it has been shown that the CL2 cells possess the wild-type sequence of p53 gene and do not lose its expression (50).…”

“…Thus far, the effects of HCV core on the cell cycle profile and cell cycle-related molecules have been studied by a few investigators (21,22,35). It has been reported that the HCV core can * The costs of publication of this article were defrayed in part by the payment of page charges.…”

“…The stable transfectant with HCV core-expressing plasmid derived from Chinese hamster ovary cells has also been shown to impair the cell cycle regulation accompanied by enhancement of p21 CIP1 expression (35). However, molecular mechanisms concerning HCV core-mediated modulation on the cell cycle-related molecules other than the p53/p21 CIP1 system have not been elucidated.…”