title: Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition.
abstract: Here we demonstrate for the first time that targeted inhibition of nuclear exporter protein exportin 1 (XPO1) also known as chromosome maintenance region 1 (CRM1) by Selective Inhibitor of Nuclear Export (SINE) compounds results in reversal of EMT in snail-transduced primary human mammary epithelial cells (HMECs). SINE compounds selinexor (KPT-330) and KPT-185, leptomycin B (LMB as +ve control) but not KPT-301 (-ve control) reverse EMT, suppress mesenchymal markers and consequently induce growth inhibition, apoptosis and prevent spheroid formation. SINE treatment resulted in nuclear retention of snail regulator FBXL5 that was concurrent with suppression of snail and down-regulation of mesenchymal markers. FBXL5 siRNA or transfection with cys528 mut-Xpo1 (lacking SINE binding site) markedly abrogated SINE activity highlighting an XPO1 and FBXL5 mediated mechanism of action. Silencing XPO1 or snail caused re-expression of FBXL5 as well as EMT reversal. Pathway analysis on SINE treated HMECs further verified the involvement of additional F-Box family proteins and confirmed the suppression of snail network. Oral administration of selinexor (15 mg/kg p.o. QoDx3/week for 3weeks) resulted in complete cures (no tumor rebound at 120 days) of HMLER-Snail xenografts. These findings raise the unique possibility of blocking EMT at the nuclear pore.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Irfana
authors.initials: I
authors.lastname: Muqbil
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Jack
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.affiliation: Karyopharm Therapeutics Newton Massachusetts, USA.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Karyopharm Therapeutics Newton Massachusetts, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Aliccia
authors.initials: A
authors.lastname: Bollig-Fischer
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dyson
authors.affiliation: Karyopharm Therapeutics Newton Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics Newton Massachusetts, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics Newton Massachusetts, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit MI 48201.|iTRI Hamad Medical Corporation, Doha Qatar.
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D028884:Karyopherins / Q000378:metabolism*; D061986:MCF-7 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C585161:selinexor; C038753:leptomycin B