title: Amplification activation loop between caspase-8 and -9 dominates artemisinin-induced apoptosis of ASTC-a-1 cells.
abstract: Although caspases have been demonstrated to be involved in artemisinin (ARTE)-induced apoptosis, their exact functions are not well understood. The aim of this report is to explore the roles of caspase-8, -9 and -3 during ARTE-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cells. ARTE treatment induces a rapid generation of reactive oxygen species (ROS), and ROS-dependent apoptosis as well as the activation of caspase-8, -9 and -3 via time- and dose-dependent fashion. Of upmost importance, inhibition of caspase-8 or -9, but not caspase-3, almost completely blocks the ARTE-induced not only activation of the caspase-8, -9 and -3 but also apoptosis. In addition, the apoptotic process triggered by ARTE does not involve the Bid cleavage, tBid translocation, significant loss of mitochondrial membrane potential and cytochrome c release from mitochondria. Moreover, silencing Bax/Bak does not prevent the ATRE-induced cell death as well as the activation of caspase-8, -9 and -3. Collectively, our data firstly demonstrate that ARTE triggers a ROS-mediated positive feedback amplification activation loop between caspase-8 and -9 independent of mitochondria, which dominantly mediated the ARTE-induced apoptosis via a caspase-3-independent apoptotic pathway in ASTC-a-1 cells. Our findings imply a potential to develop new derivatives from artemisinin to effectively initiate the amplification activation loop of caspases.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, South China Normal University, Guangzhou, China.
authors.forename: Fenglian
authors.initials: F
authors.lastname: Xiao
authors.forename: Weijie
authors.initials: W
authors.lastname: Gao
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Tongsheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002477:Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D037621:Artemisinins; D017382:Reactive Oxygen Species; C031327:artemisinin; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9