title: Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity.
abstract: 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.
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yangling
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Qiao
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Institute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: liuxuejiao0923@126.com.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. Electronic address: lihmd@163.com.
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D010881:Piperidones
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004148:Dioxolanes; C498077:piperlongumine; D010881:Piperidones
keywords: Anti-cancer; CRM1; Nuclear protein export; Piperlongumine