title: Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma.
abstract: Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.|Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Adyar Chennai, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Garg
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.
authors.forename: Deepika
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: Ngan B
authors.initials: NB
authors.lastname: Doan
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Chien
authors.affiliation: Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Adyar Chennai, India.
authors.forename: Trivadi S
authors.initials: TS
authors.lastname: Ganesan
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.
authors.forename: Linda Shyue Huey
authors.initials: LS
authors.lastname: Chuang
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.
authors.forename: Nachiyappan
authors.initials: N
authors.lastname: Venkatachalam
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California Los Angeles, School of Medicine, Los Angeles, CA, USA.|National University Cancer Institute, National University Hospital, Singapore, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000378:metabolism; D064107:Aurora Kinase B / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008080:Liposarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D006834:Hydrazines; D018975:Insulin-Like Growth Factor Binding Protein 5; D028884:Karyopherins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D018160:Receptors, Cytoplasmic and Nuclear; D017451:Receptors, Somatomedin; D014230:Triazoles; D000097606:Exportin 1 Protein; C000597236:IGF1R protein, human; C585161:selinexor; C576917:AURKA protein, human; C576921:AURKB protein, human
keywords: IGFBP5; cell cycle; selinexor; xenograft