Abstract
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.
Highlights
More than 60% of currently used anti-tumor drugs are natural origin or derived from natural compounds (Cragg et al, 2005)
We found that the asiatic acid induced increase of p21WAF1/CIP1 protein was associated with decreased phosphorylation of p21WAF1/CIP1
Asiatic acid increases the levels of p21WAF1/CIP1 through enhancing the stability of p21WAF1/CIP1 protein
Summary
More than 60% of currently used anti-tumor drugs are natural origin or derived from natural compounds (Cragg et al, 2005). Plant-derived compounds are important source of these nature derived anti-tumor agents. Some studies have reported the anti-tumor effect of asiatic acid. Asiatic acid was reported to enhance apoptosis and cell cycle arrest by promoting the activity of extracellular signalregulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells (Hsu et al, 2005). By generation of ROS, asiatic acid could induce apoptosis in human melanoma cells (Park et al, 2005; Xu et al, 2012). Asiatic acid could disturb the endoplasmic reticulum and alterations in calcium homeostasis to induce cell death (Gurfinkel et al, 2006). Asiatic acid has been shown to inhibit the angiogenic effects of VEGF (Kavitha et al, 2011)
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