Fujian Provincial Key Laboratory of Innovative Drug Target, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China..
National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan.
Mar Drugs. 2020 Jul 21;18(7):375. doi: 10.3390/md18070375.
12-Deacetyl-12--scalaradial, a scalarane sesterterpenoid from a marine sponge , 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--scalaradial exhibited anticancer effect on cervical cancer HeLa cells. The aim of this study was to investigate the anticancer activity of 12-deacetyl-12--scalaradial against HeLa cells and to explore the mechanism. The results from a methylthiazolyldiphenyl-tetrazolium (MTT) assay suggested that 12-deacetyl-12--scalaradial suppressed the proliferation of HeLa cells and flow cytometry analysis showed 12-deacetyl-12--scalaradial could induce the apoptosis of HeLa cells in dose- and time-dependent manner. Western blotting analysis demonstrated that 12-deacetyl-12--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--scalaradial could selectively enhance the trans-activation activity of Nur77. Furthermore, Western blotting analysis and fluorescence quenching showed that 12-deacetyl-12--scalaradial could induce the phosphorylation of Nur77 and interact with the ligand-binding domain (LBD) of Nur77. Our research confirmed 12-deacetyl-12--scalaradial as a potential agent for cervical cancer therapy and provided a view that 12-deacetyl-12--scalaradial may be a modulator of Nur77.
12-去乙酰基-12--海猪烯，一种来自海洋海绵的海猪烷倍半萜，据报道具有细胞毒性活性，对 HepG2、MCF-7 和 HCT-116 细胞均有作用。然而，目前没有研究表明 12-去乙酰基-12--海猪烯对宫颈癌 HeLa 细胞具有抗癌作用。本研究旨在探讨 12-去乙酰基-12--海猪烯对 HeLa 细胞的抗癌活性及其作用机制。甲基噻唑基四唑（MTT）检测结果表明，12-去乙酰基-12--海猪烯抑制 HeLa 细胞增殖，流式细胞术分析表明，12-去乙酰基-12--海猪烯能够剂量和时间依赖性诱导 HeLa 细胞凋亡。Western blot 分析表明，12-去乙酰基-12--海猪烯通过介导外源性途径诱导细胞凋亡，并发现其能够抑制与癌细胞死亡相关的 MAPK/ERK 通路。孤儿核受体 Nur77 作为一种重要的转录因子，在肿瘤发生发展中发挥着多样化的作用，已被认为是一种很有前途的抗癌药物靶点。双荧光素酶报告基因检测表明，12-去乙酰基-12--海猪烯能够选择性增强 Nur77 的转录激活活性。此外，Western blot 分析和荧光猝灭实验表明，12-去乙酰基-12--海猪烯能够诱导 Nur77 的磷酸化，并与 Nur77 的配体结合域（LBD）相互作用。本研究证实了 12-去乙酰基-12--海猪烯作为宫颈癌治疗的潜在药物，并提供了 12-去乙酰基-12--海猪烯可能是 Nur77 调节剂的观点。
