Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 762, Issue -, Pages 55-62Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2015.05.030
Keywords
Lupeol; BDNF; Akt/PI3K; GSK-3 beta; Caspase-3
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Funding
- Natural Science Foundation of Hubei Province [2013CFB239]
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Lupeol is a naturally available triterpenoid with selective anticancerous potential on various human cancer cells. The present study shows that lupeol can inhibit cell proliferation of hepatocellular carcinoma (HCC) HCCLM3 cells in a time- and dose-dependent manner, through caspase-3 dependent activation and Poly ADP-Ribose Polymerase (PARP) cleavage. Lupeol-induced cell death is associated with a marked decrease in the protein expression of Brain-Derived Neurotrophic Factor (BDNF) and ser-9-phosphoryltion of Glycogen Synthase Kinase 3 Beta (GSK-3 beta), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), beta-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110 alpha), as well as reactivation of GSK-3 beta function in HepG2 cells. Lupeol treatment also inhibits LiCl-induced activation of Wnt signaling pathway and exerts the in vitro anti-invasive activity in Huh-7 cells. LiCl-triggered high expression of beta-catenin, c-Myc and Cyclin D1 protein is reduced followed by lupeol exposure. The findings suggest a mechanistic link between caspase dependent pathway, BDNF secretion and Akt/PI3K/GSK-3 beta in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3 beta(Ser-9), cooperated with blockade of Akt/PI3K( and Wnt signaling pathway. (C) 2015 Elsevier B.V. All rights reserved.
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