Ribosomal biogenesis and translational flux inhibition by the selective inhibitor of nuclear export (sine) XPO1 antagonist KPT-185

Yoko Tabe, Kensuke Kojima, Shinichi Yamamoto, Kazumasa Sekihara, Hiromichi Matsushita, Richard Eric Davis, Zhiqiang Wang, Wencai Ma, Jo Ishizawa, Saiko Kazuno, Michael Kauffman, Sharon Shacham, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the aberrant expression of several growth-regulating, oncogenic effectors. Exportin 1 (XPO1) mediates the nucleocytoplasmic transport of numerous molecules including oncogenic growthregulating factors, RNAs, and ribosomal subunits. In MCL cells, the small molecule KPT-185 blocks XPO1 function and exerts anti-proliferative effects. In this study, we investigated the molecular mechanisms of this putative anti-tumor effect on MCL cells using cell growth/viability assays, immunoblotting, gene expression analysis, and absolute quantification proteomics. KPT-185 exhibited a p53-independent anti-lymphoma effect on MCL cells, by suppression of oncogenic mediators (e.g., XPO1, cyclin D1, c-Myc, PIM1, and Bcl-2 family members), repression of ribosomal biogenesis, and downregulation of translation/chaperone proteins (e.g., PIM2, EEF1A1, EEF2, and HSP70) that are part of the translational/transcriptional network regulated by heat shock factor 1. These results elucidate a novel mechanism in which ribosomal biogenesis appears to be a key component through which XPO1 contributes to tumor cell survival. Thus, we propose that the blockade of XPO1 could be a promising, novel strategy for the treatment of MCL and other malignancies overexpressingXPO1.

Original languageEnglish
Article numbere0137210
JournalPloS one
Volume10
Issue number9
DOIs
Publication statusPublished - 2015 Sep 4
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint

Dive into the research topics of 'Ribosomal biogenesis and translational flux inhibition by the selective inhibitor of nuclear export (sine) XPO1 antagonist KPT-185'. Together they form a unique fingerprint.

Cite this