CRM1 Is a Cellular Target of Curcumin: New Insights for the Myriad of Biological Effects of an Ancient Spice. (31st July 2013)

• Record Type: Journal Article
• Authors: Niu, Mingshan; Wu, Sijin; Mao, Lei; Yang, Yongliang
• Is Part Of: Traffic. Volume 14:Number 10(2013:Oct.)
• Page Start: 1042
• Page End: 1052
• Publication Date: 2013-07-31
• Subjects: CRM1 -- curcumin -- Michael acceptor -- nuclear protein export; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12090
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract : Curcumin, the major chemical constituent of turmeric plant, has entered clinical trial studies for its broad therapeutic properties. We present herein that CRM1, an important nuclear shuttle protein, is a cellular target of curcumin by serious experimental and theoretical investigation. The inhibition of nuclear export by curcumin may account for its myriad biological effects, particularly for its therapeutic properties in cancer and inflammatory diseases. Our findings may have important implications for further clinical investigation of curcumin. Abstract : Curcumin is the major constituent of turmeric plant, an ancient spice widely used in Indian cuisine and traditional herbal medicine. Recently, the potential medical use of curcumin as anti‐cancer and anti‐inflammatory agent has set off an upsurge in research into the mechanism for its broad biological effects. We showed that CRM1, an important nuclear exportin, is a cellular target of curcumin by serious experimental and theoretical investigation. Using a nuclear export functional assay, we observed a clear and rapid shift of cargo proteins from a cytoplasmic localization to the nucleus when treated with curcumin or its structural analogue dibenzylideneacetone (DBA). We demonstrated that curcumin could specifically target the conserved Cys 528 of CRM1 through mass spectrometric analysis and in vivo experiments. Furthermore, computational modeling has revealed that curcumin could be correctly docked into the hydrophobic pocket of CRM1 judged from shape complementarity and putative molecular interactions. The Michael acceptor moiety on curcumin is within the appropriate distance to enable Michael reaction with Cys residue of CRM1. More importantly, we showed that nuclear retention of FOXO1 could be observed in the presence of Leptomycin B (LMB) or curcumin whereas in cells expressing the CRM1‐Cys 528 mutant, only a cytoplasmic localization was observed. The inhibition of nuclear traffic by curcumin may account for its myriad of biological effects, particularly for its therapeutic properties in cancer and inflammatory diseases. Our findings may have important implications for further clinical investigation of curcumin .