Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through AKT activation: Evidence for AKT inhibition in celecoxib-induced apoptosis
Article first published online: 30 DEC 2003
Copyright © 2003 American Association for the Study of Liver Diseases
Volume 38, Issue 3, pages 756–768, September 2003
How to Cite
Leng, J., Han, C., Demetris, A. J., Michalopoulos, G. K. and Wu, T. (2003), Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through AKT activation: Evidence for AKT inhibition in celecoxib-induced apoptosis. Hepatology, 38: 756–768. doi: 10.1053/jhep.2003.50380
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 17 JUN 2003
- Manuscript Received: 15 JAN 2003
- Supported by grants from the American Liver Foundation (T.W.), the Cancer Research Foundation of America (T.W.), the National Institutes of Health (DK49615 to A.J.D.), and the Department of Pathology, University of Pittsburgh Medical Center.
Cyclooxygenase-2 (COX-2)-controlled prostaglandin (PG) metabolism recently has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). However, the biologic role and molecular mechanism of COX-2-mediated PGs in the control of liver cancer growth have not been established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth control of liver cancer cells. Human HCC cell lines Hep3B and HepG2 transfected with COX-2 expression vector showed increased cell growth and enhanced phosphorylation of serine/threonine protein kinase B (Akt). The level of COX-2 expression and Akt phosphorylation is correlated positively in cultured HCC cells and human liver cancer tissues. Inhibition of Akt activation by phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 significantly decreased the viability of Hep3B and HepG2 cells (P < .01). These results reveal a novel role of Akt activation in COX-2-induced HCC cell survival. Furthermore, HCC cells treated with the COX-2 inhibitor celecoxib showed significant reduction of Akt phosphorylation and marked morphologic and biochemical characteristics of apoptosis. Overexpression of COX-2 or addition of exogenous PGE2 partially prevented celecoxib-induced apoptosis (P < .01). In conclusion, our results suggest the involvement of COX-2-dependent and -independent mechanisms in celecoxib-mediated HCC cell apoptosis.