title: Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells.
abstract: Caffeic acid phenyl ester (CAPE) has been identified as an active component of propolis, a substance that confers diverse activities in cells of various origins. However, the molecular basis of CAPE-mediated cellular activity remains to be clarified. Here, we show that CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1). These results suggest the involvement of E2F-1 in CAPE-mediated growth inhibition and cell-cycle arrest. Transient transfection studies with luciferase reporters revealed that CAPE altered the transcriptional activity of the apaf-1 and mcl-1 promoters. Further studies using chromatin immunoprecipitation assays demonstrated that E2F-1 binding to the apaf-1 and cyclin B promoters was increased and decreased, respectively, in CAPE-treated cells. Furthermore, E2F-1 silencing abolished CAPE-mediated effects on cell-cycle arrest, apoptosis and related gene expression. Taken together, these results indicate a crucial role for E2F-1 in CAPE-mediated cellular activities in cervical cancer cells.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tzu-Hui
authors.initials: TH
authors.lastname: Hsu
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Chu
authors.forename: Mei-Whey
authors.initials: MW
authors.lastname: Hung
authors.forename: Hwei-Jen
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hsien-Jun
authors.initials: HJ
authors.lastname: Hsu
authors.forename: Tsu-Chung
authors.initials: TC
authors.lastname: Chang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002109:Caffeic Acids / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D002109:Caffeic Acids; D054697:Cytostatic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol