title: Novel reversible selective inhibitor of nuclear export shows that CRM1 is a target in colorectal cancer cells.
abstract: Colorectal cancer arises via a multistep carcinogenic process and the deregulation of multiple pathways. Thus, the simultaneous targeting of multiple pathways may be a promising therapeutic approach for colorectal treatment. CRM1 is an attractive cancer drug target, because it can regulate multiple pathways and tumor suppressor proteins. In this study, we investigated the anti-tumor activity of a novel reversible CRM1 inhibitor S109 in colorectal cancer. Our data demonstrate that S109 inhibits proliferation and induces cell cycle arrest in colorectal cancer cells. Mechanistically, we demonstrate that the activity of S109 is associated with the nuclear retention of major tumor suppress proteins. Furthermore, the Cys528 mutation of CRM1 prevented the ability of S109 to block nuclear export and inhibit the proliferation of colorectal cancer cells. Interestingly, S109 decreased the CRM1 protein level via proteasomal pathway. We argue that reversible CRM1 inhibitors but not irreversible inhibitors can induce the degradation of CRM1, because the dissociation of reversible inhibitors of CRM1 changes the conformation of CRM1. Taken together, these findings demonstrate that CRM1 is a valid target for the treatment of colorectal cancer and provide a basis for the development of S109 therapies for colorectal cancer.
authors.affiliation: a Blood Diseases Institute; Jiangsu Key Laboratory of Bone Marrow Stem Cell; Xuzhou Medical College ; Xuzhou , Jiangsu , China.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Niu
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chong
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D000097606:Exportin 1 Protein
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003517:Cyclopentanes; D028884:Karyopherins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C000608262:S109 compound; C091775:ran-binding protein 1
keywords: CRM1; CRM1, chromosomal region maintenance 1; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; LMB, leptomycin B; NES, leucine-rich nuclear export signal; PI3K, phosphoinositide 3-kinase; RanBP1, Ran-binding protein 1; S109; colorectal cancer; nuclear export; proliferation