title: CRM1/XPO1 is associated with clinical outcome in glioma and represents a therapeutic target by perturbing multiple core pathways.
abstract: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative.
  
  
  
  In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model.
  
  
  
  We found that high expression of CRM1 in glioma is a predictor of short overall survival and poor patient outcome. Our data demonstrate that S109 significantly inhibits the proliferation of human glioma cells by inducing cell cycle arrest at the G1 phase. Notably, we observed that high-grade glioma cells are more sensitive to S109 treatment compared with low-grade glioma cells. In an intracranial mouse model, S109 significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Mechanistically, S109 treatment simultaneously perturbed the three core pathways (the RTK/AKT/Foxos signaling pathway and the p53 and Rb1 tumor-suppressor pathways) implicated in human glioma cells by promoting the nuclear retention of multiple tumor-suppressor proteins.
  
  
  
  Taken together, our study highlights the potential role of CRM1 as an attractive molecular target for the treatment of human glioma and indicates that CRM1 inhibition by S109 might represent a novel treatment approach.
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Nanjing Durm Tower Hospital Group, Suqian City People's Hospital, Suqian, Jiangsu, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chong
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Yue
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Zhenglei
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Huize
authors.initials: H
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Bone Marrow Stem Cell, Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of Bone Marrow Stem Cell, Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. msniu24@126.com.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China. yu.rutong@163.com.|Brain Hospital, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. yu.rutong@163.com.
authors.forename: Rutong
authors.initials: R
authors.lastname: Yu
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology*; D019204:GTP-Binding Proteins; D005910:Glioma / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D051379:Mice; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D056286:Retinoblastoma Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D000631:Aminopyridines; D051017:Apoptosis Regulatory Proteins; D003517:Cyclopentanes; D019204:GTP-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D056286:Retinoblastoma Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000097606:Exportin 1 Protein; C000606393:RB1 protein, human; C100494:RTKN protein, human; C000608262:S109 compound
keywords: CRM1 inhibitor; Cell cycle; Glioma; Proliferation; S109