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Int. J. Mol. Sci. 2016, 17(11), 1787; doi:10.3390/ijms17111787

Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction

1
Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
2
Department of Biomedical Sciences and Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
3
Division of Pediatric Infectious Disease, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo 33305, Taiwan
4
Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan
5
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
6
Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Masato Matsuoka
Received: 2 May 2016 / Revised: 29 August 2016 / Accepted: 12 October 2016 / Published: 27 October 2016
(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress 2016)
View Full-Text   |   Download PDF [5652 KB, uploaded 27 October 2016]   |  

Abstract

Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress response and protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulated expression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated with growth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)–activating transcription factor (ATF) 6–CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)–c-Jun N-terminal kinase (JNK)–cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxic effects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways. View Full-Text
Keywords: 11-epi-sinulariolide acetate; mitochondrial dysfunction; ER stress; antitumor; hepatocellular carcinoma 11-epi-sinulariolide acetate; mitochondrial dysfunction; ER stress; antitumor; hepatocellular carcinoma
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MDPI and ACS Style

Lin, J.-J.; Wang, R.Y.L.; Chen, J.-C.; Chiu, C.-C.; Liao, M.-H.; Wu, Y.-J. Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction. Int. J. Mol. Sci. 2016, 17, 1787.

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