Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

Oncotarget. 2017 Jan 31;8(5):7521-7532. doi: 10.18632/oncotarget.13485.

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.

Keywords: IGFBP5; cell cycle; selinexor; xenograft.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Exportin 1 Protein
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydrazines / pharmacology*
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism
  • Karyopherins / antagonists & inhibitors*
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Liposarcoma / drug therapy*
  • Liposarcoma / genetics
  • Liposarcoma / metabolism
  • Liposarcoma / pathology
  • Male
  • Mice
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Receptor, IGF Type 1
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Somatomedin / metabolism
  • Signal Transduction / drug effects
  • Time Factors
  • Transfection
  • Triazoles / pharmacology*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Hydrazines
  • IGF1R protein, human
  • Insulin-Like Growth Factor Binding Protein 5
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Somatomedin
  • Triazoles
  • selinexor
  • Receptor, IGF Type 1
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B
  • Proto-Oncogene Proteins c-akt