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.

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

“…UA-mediated ATP depletion induces energy stress that resulted in AMP-activated protein kinase (AMPK) activation in breast cancer cells that in turn promoted cytotoxic autophagy and apoptosis (this study). UA-induced AMPK activation also contributed to growth inhibition and apoptosis in T24 bladder cancer cells [50] and hepatoma HepG2 cells [51, 52], and autophagy in U87MG glioma cells [37]. More recently, AMPK was found to be a negative regulator of aerobic glycolysis and a suppressor of tumor growth in vivo [53].…”

Ursolic acid and mechanisms of actions on adipose and muscle tissue: a systematic review

“…Moreover, there was an increase in the AMPK level through the inhibition of the liver kinase B1, suggesting a potential anti‐obesity effect of UA . Although numerous evidence has shown the role of UA on anti‐obesity effects and comorbidities , beneficial effects have also been described for various diseases, such as the inhibition of tumour growth , sepsis attenuation , ageing , human immunodeficiency virus , inflammation and rheumatoid arthritis . Table systematically describes the studies that used UA in the modulation of adiposity in both rodents and humans.…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Reactivation of AMPKα1 could significantly decrease the proliferative ability of hepatocellular carcinoma cells [15]. Additionally, miR-301a-mediated depression of AMPKα1 is partially contributing to the chemoresistance of doxorubicin in osteosarcoma cells [16].…”