title: Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer.
abstract: BACKGROUND
  Ovarian cancer represents the most fatal type of gynecological malignancies. Unfortunately, there are still no effective targeted treatment strategies for ovarian cancer. Overexpression of CRM1 has been correlated with poor prognosis of patients with ovarian cancer.
  
  
  OBJECTIVE
  In this study, we investigated the antitumor effects of a novel reversible inhibitor of CRM1 in ovarian cancer cells.
  
  
  METHODS
  The effects of S109 on proliferation was detected by CCK-8, EdU, clonogenic assay. The protein expression were determined by Western blot. The subcellular localization of RanBP1 was analyzed by immunofluorescence microscopy assay.
  
  
  RESULTS
  We demonstrated that S109 could induce nuclear accumulation of RanBP1, a canonical biomarker for CRM1 inhibition. This effect was clearly reversible in the majority of the cells, whereas the inhibitory effect of LMB could not be reversed. Our data reveal that treatment with S109 results in decrease in proliferation and colonogenic capacity of ovarian cancer cells by arresting cell cycle. Mechanistically, S109 treatment increase the expression of the cyclin-dependent kinase inhibitor p21, while it reduced the expression of cell cycle promoting proteins, Cyclin D1 and Cyclin B. CRM1 level itself was also down-regulated following S109 treatment. Furthermore, the nuclei of cells incubated with S109 accumulated tumor suppressor proteins (Foxo1, p27 and IκB-α). More importantly, Cys528 mutation of CRM1 abolished the ability of S109 to block proliferation of ovarian cancer cells.
  
  
  CONCLUSIONS
  Together, our study identifies CRM1 as a valid target in ovarian cancer and provides a basis for the development of S109 in ovarian cancer.
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China.|Insititute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chong
authors.affiliation: Insititute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Huize
authors.initials: H
authors.lastname: Liu
authors.affiliation: Dalian Center for Disease Control and Prevention, Dalian, Liaoning, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China. msniu24@126.com.|Department of Hematology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China. msniu24@126.com.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000096:biosynthesis; D019938:Cyclin D1; D003517:Cyclopentanes / Q000008:administration & dosage*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000097606:Exportin 1 Protein
chemical_list: D000631:Aminopyridines; D019926:Cyclin B; D019938:Cyclin D1; D003517:Cyclopentanes; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C000608262:S109 compound