12-Deacetyl-12-epi-Scalaradial, a Scalarane Sesterterpenoid from a Marine Sponge Hippospongia sp., Induces HeLa Cells Apoptosis via MAPK/ERK Pathway and Modulates Nuclear Receptor Nur77

• Published in: Marine drugs 2020-07, Vol.18 (7), p.375
• Main Authors: Zhou, Mi, Peng, Bo-Rong, Tian, Wenjing, Su, Jui-Hsin, Wang, Guanghui, Lin, Ting, Zeng, Dequan, Sheu, Jyh-Horng, Chen, Haifeng
• Format: Article
• Language: English
• Subjects: 12-deacetyl-12-epi-scalaradial; Animals; Anticancer properties; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Cancer; Cell death; Cell proliferation; Cell Proliferation - drug effects; Cervical cancer; Cervix; Cytotoxicity; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Flow cytometry; Fluorescence; HeLa Cells; Hippospongia; Humans; Kinases; Ligands; MAP kinase; MAPK/ERK pathway; Marine invertebrates; Metabolic pathways; Natural products; Neoplasms; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Nuclear receptors; Nur77; Nur77 protein; Orphan nuclear receptors; Phosphorylation; Porifera - chemistry; Proliferation; Proteins; Receptors; Sesterterpenes - isolation & purification; Sesterterpenes - pharmacology; Signal Transduction; Therapeutic targets; Time dependence; Transcription; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - enzymology; Uterine Cervical Neoplasms - pathology; Western blotting
• ISSN: 1660-3397; 1660-3397
• 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.