Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185.
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4560410?pdf=render |
| _version_ | 1828823503391948800 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yoko Tabe |
| collection | DOAJ |
| description | 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, novel strategy for the treatment of MCL and other malignancies overexpressing XPO1. |
| first_indexed | 2024-12-12T13:35:52Z |
| format | Article |
| id | doaj.art-ffb823f8503d4ea8842e83150d207de8 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T13:35:52Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ffb823f8503d4ea8842e83150d207de82022-12-22T00:22:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013721010.1371/journal.pone.0137210Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185.Yoko TabeKensuke KojimaShinichi YamamotoKazumasa SekiharaHiromichi MatsushitaRichard Eric DavisZhiqiang WangWencai MaJo IshizawaSaiko KazunoMichael KauffmanSharon ShachamTsutomu FujimuraTakashi UenoTakashi MiidaMichael AndreeffMantle 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, novel strategy for the treatment of MCL and other malignancies overexpressing XPO1.http://europepmc.org/articles/PMC4560410?pdf=render |
| spellingShingle | 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 Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. PLoS ONE |
| title | Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. |
| title_full | Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. |
| title_fullStr | Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. |
| title_full_unstemmed | Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. |
| title_short | Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185. |
| title_sort | ribosomal biogenesis and translational flux inhibition by the selective inhibitor of nuclear export sine xpo1 antagonist kpt 185 |
| url | http://europepmc.org/articles/PMC4560410?pdf=render |
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