title: Nuclear retention of Fbw7 by specific inhibitors of nuclear export leads to Notch1 degradation in pancreatic cancer.
abstract: Chromosome maintenance region 1 (CRM1) also called Exportin 1 (Xpo1), a protein found elevated in pancreatic ductal adenocarcinoma (PDAC), blocks tumor suppressor protein (TSP) function through constant nuclear export. Earlier we had shown that targeting CRM1 by our newly developed specific inhibitors of nuclear export (SINE) leads to inhibition of pancreatic cancer cell proliferation and tumor growth arrest. In this paper we define the mechanism of SINE action. Our lead SINE KPT-185 inhibits PDAC cell growth, cell migration, tumor invasion and induces apoptosis and G2-M cell cycle arrest in low nano molar range (IC50s~150 nM). Mechanistically we demonstrate that the activity of KPT-185 is associated with nuclear retention of Fbw7; which degrades nuclear Notch-1 leading to decreased tumor promoting markers such as C-Myc, Cyclin-D1, Hes1 and VEGF. The orally bioavailable SINE (KPT-251) showed potent anti-tumor activity in a Colo-357 PDAC xenografts model; residual tumor analysis showed activation of Fbw7 concomitant with attenuation of Notch1 and its downstream genes. These results suggest that the antitumor activity of KPT-185 is in part due to nuclear retention of Fbw7 and consequent Notch1 degradation. The new CRM1 inhibitors, therefore, hold strong potential and warrant further clinical investigations for PDAC.
authors.affiliation: Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan, People's Republic of China.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Gao
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Abdul-Badi
authors.initials: AB
authors.lastname: Abou-Samra
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D028884:Karyopherins; D051881:Receptor, Notch1; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D044767:Ubiquitin-Protein Ligases; D000097606:Exportin 1 Protein; C513273:FBXW7 protein, human; C576639:KPT-185; C497761:NOTCH1 protein, human