Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells.
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.
Honda
M
M
First Department of Internal Medicine, Kanazawa University, Kanazawa, Japan. mhonda@medf.m.kanazawa-u.ac.jp
Kaneko
S
S
Shimazaki
T
T
Matsushita
E
E
Kobayashi
K
K
Ping
L H
LH
Zhang
H C
HC
Lemon
S M
SM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D006224:Cricetinae; D016895:Culture Media, Serum-Free; D005260:Female; D016174:Hepacivirus / Q000378:metabolism*; D051379:Mice; D010053:Ovary / Q000166:cytology* / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D014758:Viral Core Proteins / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D016271:Proto-Oncogene Proteins c-myc; D014758:Viral Core Proteins