title: Cytotoxicity of 11-epi-Sinulariolide Acetate Isolated from Cultured Soft Corals on HA22T Cells through the Endoplasmic Reticulum Stress Pathway and Mitochondrial Dysfunction.
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 coralSinularia 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 ofgrowth arrest and DNA damage-inducible protein(GADD153) andCCAAT/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.
authors: Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. q87634@hotmail.com.
authors: Jen-Jie
authors: JJ
authors: Lin
authors: Department of Biomedical Sciences and Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan. yuwang@mail.cgu.edu.tw.|Division of Pediatric Infectious Disease, Department of Pediatrics, Chang Gung Memorial Hospital, Linkuo 33305, Taiwan. yuwang@mail.cgu.edu.tw.
authors: Robert Y L
authors: RY
authors: Wang
authors: Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan. x00000017@meiho.edu.tw.
authors: Jiing-Chuan
authors: JC
authors: Chen
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. woodnettle2002@gmail.com.
authors: Chien-Chih
authors: CC
authors: Chiu
authors: Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan. mhliao@mail.npust.edu.tw.
authors: Ming-Hui
authors: MH
authors: Liao
authors: Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan. wyr924@ms24.hinet.net.|Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan. wyr924@ms24.hinet.net.
authors: Yu-Jen
authors: YJ
authors: Wu
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D000873:Anthracenes / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage; D004224:Diterpenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000873:Anthracenes; D002934:Cinnamates; C497249:DDIT3 protein, human; D004224:Diterpenes; C496827:salubrinal; D051742:Transcription Factor CHOP; C432165:pyrazolanthrone; C050253:sinulariolide; D048031:JNK Mitogen-Activated Protein Kinases; D013890:Thiourea
keywords: 11-epi-sinulariolide acetate; ER stress; antitumor; hepatocellular carcinoma; mitochondrial dysfunction