CRM1 Is a Cellular Target of Curcumin: New Insights for the Myriad of Biological Effects of an Ancient Spice
CRM1 Is a Cellular Target of Curcumin: New Insights for the Myriad of Biological Effects of an Ancient Spice
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DOI：
10.1111/tra.12090
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发表时间：
2013-10-01
期刊：
影响因子：
4.5
通讯作者：
Yang, Yongliang
中科院分区：
文献类型：
--
作者：
Niu, Mingshan;Wu, Sijin;Yang, Yongliang
姜黄素是姜黄植物的主要成分，姜黄植物是一种古老的香料，广泛用于印度美食和传统草药。近年来，姜黄素作为抗癌和抗炎药物的潜在医学用途掀起了对其广泛生物学作用机制的研究热潮。通过大量的实验和理论研究，我们发现CRM 1 e是姜黄素的细胞靶点，CRM 1 e是一种重要的核输出蛋白。使用核输出功能测定，我们观察到货物蛋白从细胞质定位到细胞核的明确和快速的转变时，姜黄素或其结构类似物二亚苄基丙酮（DBAE）处理。我们通过质谱分析和体内实验证明姜黄素可以特异性靶向CRM 1 e的保守Cys（528）。此外，计算模型表明，姜黄素可以正确对接到CRM 1 e的疏水口袋判断从形状互补性和假定的分子相互作用。姜黄素上的迈克尔受体部分在适当的距离内，以使其能够与CRM 1 e的Cys残基发生迈克尔反应。更重要的是，我们发现，在存在Leptomycin B（LMBe）或姜黄素的情况下，可以观察到FOXO 1 e的核保留，而在表达CRM 1 e-Cys（528）突变体的细胞中，仅观察到细胞质定位。姜黄素对核运输的抑制可能是其无数生物学效应的原因，特别是其在癌症和炎性疾病中的治疗特性。我们的研究结果可能对姜黄素的进一步临床研究具有重要意义。
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 CRM1e, 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 (DBAe). We demonstrated that curcumin could specifically target the conserved Cys(528) of CRM1e through mass spectrometric analysis and in vivo experiments. Furthermore, computational modeling has revealed that curcumin could be correctly docked into the hydrophobic pocket of CRM1e 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 CRM1e. More importantly, we showed that nuclear retention of FOXO1e could be observed in the presence of Leptomycin B (LMBe) or curcumin whereas in cells expressing the CRM1e-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.