Terrein induces apoptosis in HeLa human cervical carcinoma cells through p53 and ERK regulation

Terrein, a fungal metabolite derived from Aspergillus terreus, has been shown to have a variety of biological activities in human cells including inhibition of melanogenesis, as well as anti-inflammatory, antioxidant and anticancer properties. In the present study, terrein was shown to have marked anticancer activity on HeLa human cervical carcinoma cells. Terrein exhibited inhibition of proliferation within the same ranges for other cancer cell types with an IC50 at 0.29 mM. The growth inhibition that induced cell death was via apoptosis mechanisms. Chromatin condensation was observed using the Hoechst 33342 stain, a DNA-specific dye. The increase of DNA fragmentation or the sub-GO peak was also detected by flow cytometry. The signaling used by terrein to induce apoptosis was via the death-receptor and mitochondrial pathways; the cleavage of specific fluorogenic substrates by caspase-3, -8 and -9 activities are clearly demonstrated. The mitochondria were damaged as demonstrated by the decrease of the red/green ratio of the JC-1 staining and the increase of the Bax/Bcl-2 expression ratio. Further analysis of the upstream signaling by the quantitative real-time polymerase chain reaction showed that p53, p21 and ERK were upregulated which indicates the importance of their roles on terrein signaling. This study is the first to show that terrein has an effect on the anticancer properties in cervical cancer cells by inducing apoptosis through p53 and ERK regulation. Our data may help expand the function of the terrein compound and may also aid in the discovery of new anticancer agents.