FEBS Journal, Accepted Article
Caffeic acid phenyl ester (CAPE) has been identified as an
active component of propolis, a substance that confers a variety of cellular
activities in cells of different 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 in cervical cancer cells as there is no CAPE-mediated
induction of E2F-1 in the precancerous cervical Z172 cells. CAPE also
upregulated the E2F-1 target genes cyclin A, cyclin E, and apoptotic protease
activation of factor 1 (Apaf-1) but down regulated cyclin B and myeloid
leukemia cell differentiation protein (Mcl-1). These results suggested the
involvement of E2F-1 in CAPE-mediated growth inhibition and cell cycle arrest.
Transient transfection studies with luciferase reporters revealed that CAPE
altered transcriptional activity of the apaf-1 and mcl-1 promoters. Further
studies using chromatin immunoprecipitation (ChIP) assays demonstrated that in
CAPE-treated cells, E2F-1 binding to the apaf-1 and cyclin B promoters was
increased and decreased, respectively. 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.
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