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

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