Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells

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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 (ΔΨm), 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. © 2012 by the authors; licensee MDPI.

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Su, T. R., Tsai, F. J., Lin, J. J., Huang, H. H., Chiu, C. C., Su, J. H., … Wu, Y. J. (2012). Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells. Marine Drugs, 10(8), 1883–1898. https://doi.org/10.3390/md10081883

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