Induction of Apoptosis by 11-Dehydrosinulariolide via Mitochondrial Dysregulation and ER Stress Pathways in Human Melanoma Cells

Marine Drugs

Tzu-Rong Su⁵  Feng-Jen Tsai³  Jen-Jie Lin⁴  Han Hsiang Huang³  Chien-Chih Chiu¹  Jui-Hsin Su²  Ya-Ting Yang⁶  Jeff Yi-Fu Chen¹  Bing-Sang Wong⁵ 

[1] Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80761, Taiwan;National Museum of Marine Biology and Aquarium, Pingtung 94446, Taiwan;Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan;Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan;Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan;Chemistry Department, National Sun Yat-Sen University, No. 70, Lienhai Rd., Kaohsiung 80424, Taiwan;

关键词: melanoma;    11-dehydrosinulariolide;    mitochondrial dysregulation;    ER stress;   

DOI  :  10.3390/md10081883

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.