Haplophytin-A induces caspase-8-mediated apoptosis via the formation of death-inducing signaling complex in human promyelocytic leukemia HL-60 cells |
| |
| Authors: | Kyung-Jae Won Kyung-Sook Chung Yong Sup Lee Muhammad Shaiq Alia Muhammad Kashif Pervez Samreen Fatima Jung-Hye Choi Kyung-Tae Lee |
| |
| Affiliation: | 1. School of Chemical Science and Technology, Yunnan University, Kunming 650091, Yunnan, China;2. Biomedical Engineering Research Center, Kunming Medical University, Kunming 650500, China;1. Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Klinik und Hochschulambulanz für Neurologie, Berlin, Germany;2. Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Cluster of Excellence NeuroCure, Berlin, Germany;3. Berlin Institute of Health, 10178 Berlin, Germany;4. Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Center for Stroke Resarch Berlin, Berlin, Germany;5. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany;6. DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany |
| |
| Abstract: | Haplophytin-A (10-methoxy-2,2-dimethyl-2,6-dihydro-pyrano[3,2-c]quinolin-5-one), a novel quinoline alkaloid, was isolated from the Haplophyllum acutifolium. In this study, we investigated the effect of haplophytin-A on the apoptotic activity and the molecular mechanism of action in human promyelocytic leukemia HL-60 cells. Treatment with haplophytin-A (50 μM) induced classical features of apoptosis, such as, DNA fragmentation, DNA ladder formation, and the externalization of annexin-V-targeted phosphatidylserine residues in HL-60 cells. In addition, haplophytin-A triggered the activations of caspase-8, -9, and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP) in HL-60 cells. In addition, haplophytin-A caused the loss of mitochondrial membrane potential (ΔΨm) and the release of cytochrome c and Smac/DIABLO to the cytosol, and modulated the expression levels of Bcl-2 family proteins. We further demonstrated that knockdown of caspase-8 using its siRNA inhibited the mitochondrial translocation of tBid, the activations of caspase-9 and caspase-3, and subsequent DNA fragmentation by haplophytin-A. Furthermore, haplophytin-A-induced the formation of death-inducing signaling complex (DISC) and then activated caspase-8 in HL-60 cells. During haplophytin-A-induced apoptosis, caspase-8-stimulated tBid provide a link between the death receptor-mediated extrinsic pathway and the mitochondria- mediated intrinsic pathway. Taken together, these results suggest that the novel compound haplophytin-A play therapeutical role for leukemia via the potent apoptotic activity through the extrinsic pathway, involving the intrinsic pathway. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
