title: Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1.
abstract: Hepatocellular carcinoma (HCC), the major histological subtype of primary liver cancer, remains one of the most common malignancies worldwide. Due to the complicated pathogenesis of this malignancy, the outcome for comprehensive treatment is limited. Chinese herbal medicine (CHM) is emerging as a promising choice for its multi-targets and coordinated intervention effects against HCC. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid found in CHM, exerts anti-tumor effects and is emerging as an effective compound for cancer prevention and therapy. However, the molecular mechanisms underlying the action of UA remain largely unknown. In this study, we showed that UA inhibited the growth of HCC cells and induced apoptosis in the dose- and time-dependent fashion. Furthermore, we found that UA induced phosphorylation of AMP-activated protein kinase alpha (AMPKα) and suppressed the protein expression of DNA methyltransferase 1 (DNMT1) in the dose-dependent manner. The inhibitor of AMPK, compound C blocked, while an activator of AMPK, metformin augmented the effect of UA on DNMT1 expression. In addition, UA suppressed the expression of transcription factor Sp1. Conversely, overexpression of Sp1 reversed the effect of UA on DNMT1 expression and cell growth. Collectively, our results show for the first time that UA inhibits growth of HCC through AMPKα-mediated inhibition of Sp1; this in turn results in inhibition of DNMT1. This study reveals a potential novel mechanism by which UA controls growth of HCC cells and suggests that DNMT1 could be novel target for HCC chemoprevention and treatment.
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, 510120, Guangdong, China.
authors.forename: Yinyi
authors.initials: Y
authors.lastname: Yie
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
authors.forename: Qin
authors.initials: Q
authors.lastname: Tang
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: LiJuan
authors.initials: L
authors.lastname: Yang
authors.forename: ShiGuan
authors.initials: S
authors.lastname: Deng
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008687:Metformin / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D055372:AMP-Activated Protein Kinases; D000972:Antineoplastic Agents, Phytogenic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D008687:Metformin; D016329:Sp1 Transcription Factor; D014315:Triterpenes; D000097245:Ursolic Acid; C108209:SP1 protein, human; C000619380:DNMT1 protein, human