title: A novel mechanism of hepatocellular carcinoma cell apoptosis induced by lupeol via Brain-Derived Neurotrophic Factor Inhibition and Glycogen Synthase Kinase 3 beta reactivation.
abstract: 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-3β), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), β-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110α), as well as reactivation of GSK-3β 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 β-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-3β in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3β(Ser-9), cooperated with blockade of Akt/PI3K and Wnt signaling pathway.
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Wuhan University School of Basic Medical Sciences, Wuhan, People's Republic of China. Electronic address: whuqq@hotmail.com.
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Qiu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004793:Enzyme Reactivators / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism; D000094042:Lupanes
chemical_list: D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D053148:Caspase 3; D004793:Enzyme Reactivators; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D051176:beta Catenin; C579455:BDNF protein, human; C000605506:GSK3B protein, human; C010480:lupeol; D000094042:Lupanes
keywords: Akt/PI3K; BDNF; Caspase-3; GSK-3β; Lupeol