CRM1 Is a Direct Cellular Target of the Natural Anti-cancer Agent Plumbagin
CRM1 Is a Direct Cellular Target of the Natural Anti-cancer Agent Plumbagin
复制标题
CRM1 是天然抗癌剂白花丹素的直接细胞靶标
DOI：
10.1254/jphs.13240fp
复制
发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Xu, Kailin
中科院分区：
文献类型：
--
作者：
Liu, Xuejiao;Niu, Mingshan;Xu, Kailin
白花丹素是一种来源于药用植物白花丹的萘醌，已显示在体外以及动物肿瘤模型中发挥抗癌和抗增殖活性。然而，其抗肿瘤作用的机制仍不清楚。CRM1是一种核输出受体，参与肿瘤抑制因子的主动转运，其功能在癌症中由于表达增加和过度活跃的转运而改变。我们发现CRM1是白花丹素的直接细胞靶点。与白花丹素孵育的细胞核积累肿瘤抑制蛋白，并抑制CRM 1和这些蛋白之间的相互作用。特别地，我们通过质谱分析证明了白花丹素可以特异性地与CRM 1的保守Cys（528）反应，但不与Cys（528）突变肽反应。更重要的是，用突变型CRM 1（C528 S）转染的癌细胞对白花丹素的抑制作用具有抗性，表明这种抑制作用是通过与CRM 1的Cys（528）直接相互作用实现的。白花丹素对核运输的抑制可能是其在癌症和炎性疾病中的治疗特性的原因。我们的发现可能有助于开发一类新的CRM 1抑制剂。
Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, has been shown to exert anti-cancer and anti-proliferative activities in vitro as well as in animal tumor models. However, the mechanism underlying its anti-tumor action still remains unclear. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors whose function is altered in cancer due to increased expression and overactive transport. We showed that CRM1 is a direct cellular target of plumbagin. The nuclei of cells incubated with plumbagin accumulated tumor-suppressor proteins and inhibited the interactions between CRM1 and these proteins. Particularly, we demonstrated that plumbagin could specifically react with the conserved Cys(528) of CRM1 but not with a Cys(528) mutant peptide through Mass spectrometric analysis. More importantly, cancer cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of plumbagin, demonstrating that the inhibition is through direct interaction with Cys(528) of CRM1. The inhibition of nuclear traffic by plumbagin may account for its therapeutic properties in cancer and inflammatory diseases. Our findings could contribute to the development of a new class of CRM1 inhibitors.