Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma

Cancer Sci. 2014 Jul;105(7):795-801. doi: 10.1111/cas.12430. Epub 2014 Jun 3.

Abstract

The nuclear transporter exportin-1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1-selective inhibitors of nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE-induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53-mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT-185 induced apoptosis in MCL cells through p53-dependent and -independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT-185-induced, p53-mediated apoptosis in the MCL cells occurred in a transcription-dependent manner. Exportin-1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT-185 effectively activates p53-mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL.

Keywords: Apoptosis; KPT-SINE; XPO1; mantle cell lymphoma; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylates / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Gene Expression Regulation, Neoplastic
  • Genes, p53*
  • Humans
  • Karyopherins / genetics
  • Karyopherins / metabolism*
  • Lymphoma, Mantle-Cell / genetics*
  • Lymphoma, Mantle-Cell / mortality
  • Lymphoma, Mantle-Cell / pathology*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Prognosis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription, Genetic
  • Triazoles / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Acrylates
  • KPT-185
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • TP53 protein, human
  • Triazoles
  • Tumor Suppressor Protein p53
  • exportin 1 protein