title: 4-O-methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21-mediated suppression of NF-κB activity.
abstract: OBJECTIVE
  The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated.
  
  
  METHODS
  The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model.
  
  
  RESULTS
  MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1)  phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues.
  
  
  CONCLUSIONS
  MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.
authors.affiliation: College of Pharmacy, Chungbuk National University, Chungbuk, South Korea.
authors.forename: N J
authors.initials: NJ
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Oh
authors.forename: J O
authors.initials: JO
authors.lastname: Ban
authors.forename: J H
authors.initials: JH
authors.lastname: Shim
authors.forename: H P
authors.initials: HP
authors.lastname: Lee
authors.forename: J K
authors.initials: JK
authors.lastname: Jung
authors.forename: B W
authors.initials: BW
authors.lastname: Ahn
authors.forename: D Y
authors.initials: DY
authors.lastname: Yoon
authors.forename: S B
authors.initials: SB
authors.lastname: Han
authors.forename: Y W
authors.initials: YW
authors.lastname: Ham
authors.forename: J T
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C542058:4-O-methylhonokiol; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017705:Lignans; D016328:NF-kappa B; D047495:PPAR gamma