title: 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.
authors.affiliation: Department of General Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou, China E-mail : drhuangzh@163.com.
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Chen
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Chen
authors.forename: Qing-Wen
authors.initials: QW
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Zong-Hai
authors.initials: ZH
authors.lastname: Huang
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C017032:asiatic acid; D017346:Protein Serine-Threonine Kinases; C491614:STK38 protein, human; C496014:STK38L protein, human