Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels

Matthew Tan, Hiromi I. Wettersten, Kristy Chu, David L. Huso, Terry Watnick, Sharon Friedlander, Yosef Landesman, Robert H. Weiss

Research output: Contribution to journalArticle

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective down-regulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G0/G1 arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBP(3 was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBPα, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1v/v. Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD.

Original languageEnglish (US)
Pages (from-to)F1179-F1186
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number11
DOIs
StatePublished - Dec 1 2014

Keywords

  • Autosomal-dominant polycystic kidney disease
  • Cell cycle
  • Cyclin-dependent kinase 4
  • Exportin 1

ASJC Scopus subject areas

  • Physiology
  • Urology

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