Anti-tumor activity of selective inhibitors of XPO1/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: the role of survivin

Oncotarget. 2015 May 30;6(15):13119-32. doi: 10.18632/oncotarget.3761.

Abstract

Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM.

Keywords: SINE; XPO1/CRM1; diffuse malignant peritoneal mesothelioma; survivin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Hydrazines / pharmacology
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Karyopherins / antagonists & inhibitors*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy*
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Mice
  • Mice, SCID
  • Neoplasm Proteins / metabolism
  • Oxadiazoles / pharmacology
  • Peritoneal Neoplasms / drug therapy*
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Survivin
  • Thiazoles / pharmacology
  • Triazoles / pharmacology
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Acrylamides
  • Antineoplastic Agents
  • BIRC5 protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Hydrazines
  • Inhibitor of Apoptosis Proteins
  • KPT-251
  • KPT-276
  • Karyopherins
  • Neoplasm Proteins
  • Oxadiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Survivin
  • Thiazoles
  • Triazoles
  • Tumor Suppressor Protein p53
  • exportin 1 protein
  • selinexor