Human fortilin is a molecular target of dihydroartemisinin

Fujita, Takayuki; Felix, Kumar; Pinkaew, Decha; Hutadilok-Towatana, Nongporn; Liu, Zhihe; Fujise, Ken

doi:10.1016/j.febslet.2008.02.055

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Volume 582, Issue 7 , Pages 1055-1060, 2 April 2008

Human fortilin is a molecular target of dihydroartemisinin

Edited by Barry Halliwell

Takayuki Fujita
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301, University Boulevard, John Sealy Annex Suite 5.160G, Galveston, TX 77555, USA
- Present address: Yokohama City University, School of Medicine, Yokohama 236-0027, Japan.
Kumar Felix
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301, University Boulevard, John Sealy Annex Suite 5.160G, Galveston, TX 77555, USA
- Present address: University of Texas, Houston Health Science Center at Houston, Houston, TX 77030, USA.
Decha Pinkaew
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301, University Boulevard, John Sealy Annex Suite 5.160G, Galveston, TX 77555, USA
- Department of Biochemistry, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, 90112, Thailand
Nongporn Hutadilok-Towatana
- Department of Biochemistry, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, 90112, Thailand
Zhihe Liu
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301, University Boulevard, John Sealy Annex Suite 5.160G, Galveston, TX 77555, USA
Ken Fujise
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 301, University Boulevard, John Sealy Annex Suite 5.160G, Galveston, TX 77555, USA
- Corresponding author. Fax: +1 409 419 1777.

Received 17 February 2008; received in revised form 23 February 2008; accepted 25 February 2008. published online 04 March 2008.

Abstract

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.

Abbreviations: DHA, dihydroartemisinin, TCTP, translationally controlled tumor protein, HRP, histamine releasing factor, ANOVA, analysis of variance, SPR, surface plasmon resonance