Human fortilin is a molecular target of dihydroartemisinin.
Dehydroartemisinin (DHA) is an effective anti-malaria agent. Fortilin is an anti-apoptotic molecule overexpressed in many human cancers. Here, we show that DHA binds human fortilin, increases the ubiquitination of fortilin, shortens fortilin's half-life in a proteasome-dependent fashion, and reduces cellular levels of fortilin in varieties of cells. DHA induced DNA fragmentation in U2OS cells in a fortilin-dependent manner. The fortilin-knocked-down cells were less susceptible--and fortilin-overexpressing cells more susceptible--to DHA than were wild-type cells, suggesting that apoptotic effects of DHA are-at least partly-conferred through fortilin. Together, these data suggest that fortilin is a molecular target of DHA. DHA and its derivative may prove to be viable anti-cancer agents in fortilin-overexpressing cancers.
Fujita
Takayuki
T
Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
Felix
Kumar
K
Pinkaew
Decha
D
Hutadilok-Towatana
Nongporn
N
Liu
Zhihe
Z
Fujise
Ken
K
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053938:DNA Fragmentation; D006207:Half-Life; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D000090324:Tumor Protein, Translationally-Controlled 1; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D037621:Artemisinins; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012717:Sesquiterpenes; D000090324:Tumor Protein, Translationally-Controlled 1; D025801:Ubiquitin; C039060:artenimol; D046988:Proteasome Endopeptidase Complex