title: Cryptocaryone, a natural dihydrochalcone, induces apoptosis in human androgen independent prostate cancer cells by death receptor clustering in lipid raft and nonraft compartments.
abstract: OBJECTIVE
  Androgen refractory prostate cancer is a major clinical challenge. Treatment approaches to prostate cancer are based on various mechanisms that cause malignant cell apoptosis. Of these strategies the anticancer effect of triggering death receptors is well substantiated.
  
  
  METHODS
  Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of the natural dihydrochalcone cryptocaryone in prostate cancer cells.
  
  
  RESULTS
  Cryptocaryone induced antiproliferative and apoptotic effects in human androgen independent prostate cancer cells. It induced caspase-8 and 3 activation but did not change total protein levels of death receptors and their ligands. DR5 surface expression was moderately increased by cryptocaryone. Confocal immunofluorescence examination showed that cryptocaryone induced Fas clustering and the association of downstream signaling molecules, including FADD and procaspase-8. DR4 and DR5 aggregation was also induced by cryptocaryone. Data were confirmed by protein profile analysis of detergent resistant membranes showing that Fas, DR4, DR5, FADD and procaspase-8 levels were increased 1.3, 3.5, 4.1, 13.1 and 4.1-fold, respectively, in the lipid raft compartment. Cryptocaryone mediated clustering of death receptors and associated molecules was also detected in nonraft compartments. The distribution between lipid raft and nonraft compartments was validated by the cholesterol depleting agent methyl-beta-cyclodextrin. Cryptocaryone significantly potentiated FasL induced apoptosis in PC-3 cells.
  
  
  CONCLUSIONS
  We suggest that cryptocaryone has anticancer activity via the stimulation of death receptor and associated molecule clustering, leading to caspase-8 and 3 activation, and apoptosis in prostate cancer cells.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Fan-Lu
authors.initials: FL
authors.lastname: Kung
authors.forename: Ian-Lih
authors.initials: IL
authors.lastname: Tsai
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chou
authors.forename: Ih-Sheng
authors.initials: IS
authors.lastname: Chen
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000728:Androgens; D017209:Apoptosis / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011753:Pyrones / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000187:drug effects* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D011753:Pyrones; D053218:Receptors, Death Domain; C548572:cryptocaryone