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.