title: Alpinetin suppresses proliferation of human hepatoma cells by the activation             of MKK7 and elevates sensitization to cis-diammined dichloridoplatium.
abstract: Alpinetin is a type of novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong anti-hepatoma effects. However, the detailed antitumor mechanism of alpinetin remains unclear. Mitogen-activated protein kinase kinase-7 (MKK7) can regulate cellular growth, differentiation and apoptosis. The aim of this study was to investigate the role of MKK7 in the anti-hepatoma effect mediated by alpinetin. HepG2 cells were treated with alpinetin at various doses and for different times, and the levels of phosphorylated MKK7 (p-MKK7) and total MKK7 were tested by RT-PCR and western blotting. Following transient transfection with RNA interference, cell viability and cell cycle stage were determined using methyl thiazolyl tetrazolium assay and flow cytometry, in order to assess the antitumor action of alpinetin. In addition, chemosensitization to cis-diammined dichloridoplatium (CDDP) by alpinetin was assessed by cell counting array and the cell growth inhibitory rate was calculated. The results showed that alpinetin suppressed HepG2 cell proliferation and arrested cells in the G0/G1 phase by up-regulating the expression levels of p-MKK7. On the contrary, inhibiting the expression of MKK7 reversed the antitumor effect of alpinetin. Moreover, alpinetin enhanced the sensitivity of HepG2 hepatoma cells to the chemotherapeutic agent CDDP. Taken together, our studies indicate that activation of MKK7 mediates the anti-hepatoma effect of alpinetin. MKK7 may be a putative target for molecular therapy against hepatoma and alpinetin could serve as a potential agent for the development of hepatoma therapy.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Jian
authors.initials: J
authors.lastname: Du
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wang
authors.forename: Guang
authors.initials: G
authors.lastname: Tan
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Gao
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048688:MAP Kinase Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; D044950:Flavanones; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C436748:alpinetin; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D002945:Cisplatin