title: Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein.
abstract: Nucleocytoplasmic trafficking of proteins/RNAs is essential to normal cellular function. Indeed, accumulating evidence suggests that cancer cells escape anti-neoplastic mechanisms and benefit from pro-survival signals via the dysregulation of this system. The nuclear exporter chromosome region maintenance 1 (CRM1) protein is the only protein in the karyopherin-β protein family that contributes to the trafficking of numerous proteins and RNAs from the nucleus. It is considered to be an oncogenic, anti-apoptotic protein in transformed cells, since it reportedly functions as a gatekeeper for cell survival, including affecting p53 function, and ribosomal biogenesis. Furthermore, abnormally high expression of CRM1 is correlated with poor patient prognosis in various malignancies. Therapeutic targeting of CRM1 has emerged as a novel cancer treatment strategy, starting with a clinical trial with leptomycin B, the original specific inhibitor of CRM1, followed by development of several next-generation small molecules. KPT-330, a novel member of the CRM1-selective inhibitors of nuclear export (SINE) class of compounds, is currently undergoing clinical evaluation for the therapy of various malignancies. Results from these trials suggest that SINE compounds may be particularly useful against hematological malignancies, which often become refractory to standard chemotherapeutic agents.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jo
authors.initials: J
authors.lastname: Ishizawa
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mandreef@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein
keywords: CRM1; Hematological malignancies; KPT-330; Nuclear export; Ribosomal biogenesis; SINE