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

Abstract

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-G0 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.

Isolation and Characterization of “Terrein” an Antimicrobial and Antitumor Compound from Endophytic Fungus Aspergillus terreus (JAS-2) Associated from Achyranthus aspera Varanasi, India

“…The compound has been tested against different types of cancer cell lines such as pancreatic cancer, breast cancer (Liao et al, 2012), human cervical cancer (Porameesanaporn et al, 2013) skin cancer, and prostate cancer (Arakawa et al, 2008). Among the different types of cancer identified globally, lung cancer is found to be the most prevalent type (12.7% of 1.61 million) (Ferlay et al, 2008).…”

High expression of octamer transcription factor 1 in cervical cancer

“…Specific biomarkers are required for the early diagnosis and prediction of metastatic progression and effective therapy. However, there is currently no efficient therapy against cervical cancer and the available treatments have various disadvantages (1,16–21). It has been shown that inactivation of tumor suppressor genes and activation of oncogenes is significant in carcinogenesis, and results from genetic and epigenetic alterations (5,6).…”

Terrein inhibits migration of human breast cancer cells via inhibition of the Rho and Rac signaling pathways

“…Isolation of terrein ( Fig. 1) was performed as previously described (11). Briefly, an ethyl acetate (EtOAc) extract from the culture broth of Aspergillus terreus CRI301 was concentrated in vacuo, fractioned and purified by Sephadex™ LH-20 using MeOH as an eluent.…”

“…Activation of the caspase-7 pathway and suppression of Akt signaling was observed following exposure of ABCG-2-expressing MCF-7 breast cancer cells to terrein (10). HeLa cervical cancer cells were also sensitive to the anti-proliferation activity of terrein which was mediated through induction of apoptosis (11). In addition, terrein attenuated angiogenin production in head and neck cancer cells (12), which may be another underlying mechanism in its anticancer effects.…”