Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185

PloS One
Yoko TabeMichael Andreeff

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 growth-regulating 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,...Continue Reading

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Citations

Feb 16, 2017·Journal of Hematology & Oncology·Vincent CamusFabrice Jardin
Jul 1, 2016·Signal Transduction and Targeted Therapy·Qingxiang SunDa Jia
Jul 7, 2020·Leukemia·Boaz Nachmias, Aaron D Schimmer
Jun 4, 2020·Journal of Hematology & Oncology·Nancy G Azizian, Yulin Li
Apr 23, 2021·Translational Research : the Journal of Laboratory and Clinical Medicine·Mahmoud DabbahLiat Drucker

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Datasets Mentioned

BETA
NM000546
GSE70479

Methods Mentioned

BETA
Assay
PCR
flow cytometry

Software Mentioned

Ingenuity Pathway Analysis ( IPA )
ProteinPilot
GeneGo
Metacore
ImageJ
TrEMBL

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