CRM1 Is a Direct Cellular Target of the Natural Anti-cancer Agent Plumbagin

Abstract

Abstract. 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.

CRM1 Inhibitors for Antiviral Therapy

“…Herbal products with confirmed clinical safety features are attractive starting material for the identification of new antiviral activities. Recent demonstration of anti-HIV-1 activity of extracts of Pelargonium sidoides , licensed in Germany as the herbal medicine Umckaloabo® suggests that investigation of antiviral activities among herbal extracts holds immense potential (Niu et al, 2013, 2015; Forouzanfar et al, 2014; Helfer et al, 2014; Liu X. et al, 2014; Wang et al, 2015). A selection of naturally occurring CRM1 inhibitors are described below.…”

“…It is known to induce apoptosis and cell cycle arrest by suppressing constitutive the NF-kB signal pathway (Ahmad et al, 2008). Plumbagin has been demonstrated to interfere with CRM1-mediated export, directly interacting with the transporter protein same as LMB which could explain some of its therapeutic properties (Liu X. et al, 2014). Plumbagin disrupts CRM1 export and retains tumor suppressors, such as FOXO1, p21, p53, and p73 in the nucleus suggesting this as a mechanism for the naphthoquinone's antitumorigenic effects (Liu X. et al, 2014).…”

Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer

“…An increasing number of compounds have been isolated or synthesized that inhibit CRM1 [15, 16]. However, most of them are irreversible inhibitors which have toxicity on normal cells.…”

Engineering chromosome region maintenance 1 fragments that bind to nuclear export signals

“…CRM1 inhibitors demonstrated promising potential in preclinical or clinical trials . Several CRM1 inhibitors were derived from plants including, piperlongumine (PIP), oridonin (ORI), valtrate (VAL), acetoxychavicol acetate (ACA), goniothalamin, plumbagin (PLU), sulforaphene, caffeic acid phenethyl ester, and curcumin (CUR) . Though these reports all demonstrated inhibition of CRM1 cargo's export through cellular assays, none used purified proteins to demonstrate their direct binding such as using pull‐down assays.…”