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Asiatic acid promotes p21(WAF1/CIP1) protein stability through attenuation of NDR1/2 dependent phosphorylation of p21(WAF1/ CIP1) in HepG2 human hepatoma cells.

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.
AuthorsJin-Yuan Chen, Jin-Yuan Chen, Qing-Wen Xu, Hong Xu, Zong-Hai Huang
JournalAsian Pacific journal of cancer prevention : APJCP (Asian Pac J Cancer Prev) Vol. 15 Issue 2 Pg. 963-7 ( 2014) ISSN: 2476-762X [Electronic] Thailand
PMID24568526 (Publication Type: Journal Article)
Chemical References
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Pentacyclic Triterpenes
  • RNA, Messenger
  • RNA, Small Interfering
  • asiatic acid
  • Protein Serine-Threonine Kinases
  • STK38 protein, human
  • STK38L protein, human
Topics
  • Apoptosis
  • Blotting, Western
  • Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics, metabolism)
  • Humans
  • Immunoprecipitation
  • Liver Neoplasms (drug therapy, metabolism, pathology)
  • Pentacyclic Triterpenes (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Protein Stability (drug effects)
  • RNA, Messenger (genetics)
  • RNA, Small Interfering (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

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