Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells.
Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory activity. In this study, Andro induced apoptosis in human cancer cells via activation of caspase 8 in the extrinsic death receptor pathway and subsequently with the participation of mitochondria. Andro triggered a caspase 8-dependent Bid cleavage, followed by a series of sequential events including Bax conformational change and mitochondrial translocation, cytochrome c release from mitochondria, and activation of caspase 9 and 3. Inhibition of caspase 8 blocked Bid cleavage and Bax conformational change. Consistently, knockdown of Bid protein using small interfering RNA (siRNA) technique suppressed Andro-induced Bax conformational change and apoptosis. In conclusion, the pro-apoptotic Bcl-2 family members (Bid and Bax) are the key mediators in relaying the cell death signaling initiated by Andro from caspase 8 to mitochondria and then to downstream effector caspases, and eventually leading to apoptotic cell death.
Zhou
Jing
J
Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Zhang
Siyuan
S
Ong
Choon-Nam
CN
Shen
Han-Ming
HM
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D011487:Protein Conformation; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured
D004224:Diterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C030419:andrographolide; D045304:Cytochromes c; D020169:Caspases