Abstract
12-Deacetyl-12-epi-scalaradial, a scalarane sesterterpenoid from a marine sponge Hippospongia sp, has been reported to possess cytotoxic activity on HepG2, MCF-7, and HCT-116 cells. However, there is no research to indicate that 12-deacetyl-12-epi-scalaradial exhibited anticancer effect on cervical cancer HeLa cells. The aim of this study was to investigate the anticancer activity of 12-deacetyl-12-epi-scalaradial against HeLa cells and to explore the mechanism. The results from a methylthiazolyldiphenyl-tetrazolium (MTT) assay suggested that 12-deacetyl-12-epi-scalaradial suppressed the proliferation of HeLa cells and flow cytometry analysis showed 12-deacetyl-12-epi-scalaradial could induce the apoptosis of HeLa cells in dose- and time-dependent manner. Western blotting analysis demonstrated that 12-deacetyl-12-epi-scalaradial triggered apoptosis via mediating the extrinsic pathway and was found to suppress MAPK/ERK pathway which was associate with cancer cell death. Nur77, a critical number of orphan nuclear receptors, plays diverse roles in tumor development as a transcription factor and has been considered as a promising anticancer drug target. The dual-luciferase reporter assays suggested that 12-deacetyl-12-epi-scalaradial could selectively enhance the trans-activation activity of Nur77. Furthermore, Western blotting analysis and fluorescence quenching showed that 12-deacetyl-12-epi-scalaradial could induce the phosphorylation of Nur77 and interact with the ligand-binding domain (LBD) of Nur77. Our research confirmed 12-deacetyl-12-epi-scalaradial as a potential agent for cervical cancer therapy and provided a view that 12-deacetyl-12-epi-scalaradial may be a modulator of Nur77.
Highlights
Cancer, a hyper-proliferative disorder, ranks as the primary cause of mortality worldwide.Cervical cancer, with an increasing annual incidence and mortality rate, is one of the most frequently diagnosed cancers among women globally [1]
12-deacetyl-12-epi-scalaradial was isolated from marine sponge Hippospongia sp and its chemical structure was identified by a comparison with the literature [19] (Figure 1A)
Western blotting and relative intensity analysis further confirmed that the protein level of cleaved caspase 8 was increased dose dependently after treatment with 12-deacetyl-12-epi-scalaradial in HeLa cells, and cleaved caspase 3 was observed when HeLa cells were exposed to the compound in 30 μM
Summary
A hyper-proliferative disorder, ranks as the primary cause of mortality worldwide. Many reports showed that the natural modulators of Nur could lead to apoptosis in certain cancer cells. Several other compounds targeting Nur derived from nature or synthesis were found to interact with Nur and mediate the apoptosis of cancer cells [6,7,8,9,10]. One of the unique types of terpenoid, are exclusively derived from sponges and shell less molluscs Many of these compounds have been reported to show significant antitumor activity in vitro or in vivo [13,14,15,16,17,18], while most of their mechanisms of action remain unclear. We investigated the interaction between 12-deacetyl-12-epi-scalaradial and the ligand-binding domain (LBD) of Nur
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