title: Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells.
abstract: In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis-inducing activities against A2058 melanoma cells. Anti-tumor effects of 11-dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2-8 μg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11-dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress-mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress-mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways.
authors.affiliation: Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan.
authors.forename: Tzu-Rong
authors.initials: TR
authors.lastname: Su
authors.affiliation: Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan.
authors.forename: Feng-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan.
authors.forename: Jen-Jie
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan.
authors.forename: Han Hsiang
authors.initials: HH
authors.lastname: Huang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80761, Taiwan.
authors.forename: Chien-Chih
authors.identifier: 0000-0001-7307-2468
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: National Museum of Marine Biology and Aquarium, Pingtung 94446, Taiwan.
authors.forename: Jui-Hsin
authors.initials: JH
authors.lastname: Su
authors.affiliation: Chemistry Department, National Sun Yat-Sen University, No. 70, Lienhai Rd., Kaohsiung 80424, Taiwan.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80761, Taiwan.
authors.forename: Jeff Yi-Fu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan.
authors.forename: Bing-Sang
authors.initials: BS
authors.lastname: Wong
authors.affiliation: Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C569844:11-dehydrosinulariolide; D000970:Antineoplastic Agents; D004224:Diterpenes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human