Previous studies have suggested anti-
tumor effects of
asiatic acid in some human
cancer cell lines. This agent is reported to increase the levels of p21WAF1/CIP1 in human
breast cancer cell lines. However, the molecular mechanisms have not been established. Here we report that
asiatic acid up-regulates p21WAF1/CIP1
protein expression but not the level of p21WAF1/CIP1
mRNA in HepG2 human
hepatoma cells. Furthermore, we found that the
asiatic acid induced increase of p21WAF1/CIP1
protein was associated with decreased phosphorylation (ser-146) of p21WAF1/CIP1. Knockdown of NDR1/2
kinase, which directly phosphorylates p21WAF1/CIP1
protein at ser-146 and enhances its proteasomal degradation, increased the levels of p21WAF1/CIP1
protein and eliminated the regulation of p21WAF1/ CIP1 stability by
asiatic acid. At the same time, the expression of NDR1/2
kinase decreased during treatment with
asiatic acid in HepG2 cells. Moreover,
asiatic acid inhibited the proliferation of HepG2 cells, this being attenuated by knockdown of p21WAF1/CIP1. In conclusion, we propose that
asiatic acid inhibits the expression NDR1/2
kinase and promotes the stability of p21WAF1/CIP1
protein through attenuating NDR1/2 dependent phosphorylation of p21WAF1/CIP1 in HepG2 cells.