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 G 2 /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.

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

“…The cell cycle distribution and the percentage of apoptotic cells were analyzed using propidium iodide (PI) staining as described previously. 56 Briefly, the cells (1 × 10 6 ) were washed and resuspended in 1 ml hypotonic fluorochrome solution (50 μg/ml of PI in 0.1% sodium citrate plus 0.1% Triton-X-100). The samples were placed at 4°C in the dark, and the PI fluorescence of individual nuclei was analyzed using a FACScan flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA).…”

CD133 + melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: Significance for melanoma treatment

“…melanoma specimens [1]. Then, we performed a comparative analysis of CD133 + vs CD133 − melanoma subpopulation, based on the reported anti-tumor activity of CAPE [23,24]. We first assessed the CD133 + fraction in patients' specimens by immune histochemical analysis using anti-HMB-45 and CD133 antibodies.…”

“…Whereas, in human cervical cancer cells CAPE has been reported to induce both growth inhibition and cell cycle arrest via mechanism mediated by E2F1-dependent pathways [25]. E2F1-associated apoptosis can be mediated in a p53-dependent and p53-independent manner [24]. In most cases, the induction of cell death by E2F1 occurs via direct transcriptional activation of the proapoptotic genes, including p73 [26,27], Apaf-1 [28], BH3-only proteins such as Noxa and caspases [29,30], or by the inhibition of both survival and anti-apoptotic signaling pathways regulated by NF-ƙB [31], or Bcl-2 [32].…”

“…Indeed, the success of genotoxic treatments is attributed to DNA damage that induces cell death more readily in tumor cells than in normal cells. Caffeic acid phenethyl ester (CAPE) is a bioactive component with antitumor activity reported in different tumor types [23,24]. CAPE has the potential to suppress the proliferation of human prostate cancer cells via a mechanism mediated by the inhibition of p70S6K and Akt signaling pathways [24].…”

“…Caffeic acid phenethyl ester (CAPE) is a bioactive component with antitumor activity reported in different tumor types [23,24]. CAPE has the potential to suppress the proliferation of human prostate cancer cells via a mechanism mediated by the inhibition of p70S6K and Akt signaling pathways [24]. Whereas, in human cervical cancer cells CAPE has been reported to induce both growth inhibition and cell cycle arrest via mechanism mediated by E2F1-dependent pathways [25].…”