Laboratory of Neurosurgery, Xuzhou Medical College, China.
J Pharmacol Sci. 2014;124(4):486-93. doi: 10.1254/jphs.13240fp.
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.
白花丹醌是一种来源于药用植物白花丹的萘醌，已被证明在体外和动物肿瘤模型中具有抗癌和抗增殖活性。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，由于表达增加和过度活跃的转运，其功能在癌症中发生改变。我们表明 CRM1 是白花丹醌的直接细胞靶标。与白花丹孵育的细胞的核内积累肿瘤抑制蛋白，并抑制 CRM1 与这些蛋白之间的相互作用。特别是，我们通过质谱分析证明，白花丹可以特异性地与 CRM1 的保守半胱氨酸 (Cys528) 反应，但不能与 Cys528 突变肽反应。更重要的是，转染突变 CRM1（C528S）的癌细胞对白花丹的抑制作用具有抗性，表明抑制作用是通过与 CRM1 的 Cys528 直接相互作用实现的。白花丹抑制核运输可能是其在癌症和炎症性疾病中具有治疗作用的原因。我们的发现可能有助于开发一类新的 CRM1 抑制剂。
