Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity

•Piperlongumine is a novel inhibitor of CRM1.•Piperlongumine directly binds to cysteine 528 of CRM1.•Piperlongumine inhibits the interaction between CRM1 and tumor suppressor proteins.•Piperlongumine suppresses the proliferation of cancer cells via inhibiting CRM1.

Piperlongumine is a natural compound recently identified to be toxic selectively to tumor cells in vitro and in vivo. However, the molecular mechanism underlying its anti-tumor action still remains unclear. In this report, we describe another novel mechanism by which piperlongumine mediates its anti-tumor effects. We found that piperlongumine is a novel nuclear export inhibitor. Piperlongumine could induce nuclear retention of tumor suppressor proteins and inhibit the interactions between CRM1 and these proteins. Piperlongumine could directly bind to the conserved Cys528 of CRM1 but not to a Cys528 mutant peptide. More importantly, cancer cells expressing mutant CRM1 (C528S) are resistant to piperlongumine, demonstrating the nuclear export inhibition via direct interaction with Cys528 of CRM1. The inhibition of nuclear export by piperlongumine may account for its therapeutic properties in cancer diseases. Our findings provide a good starting point for development of novel CRM1 inhibitors.