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Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor resul...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346685/ https://www.ncbi.nlm.nih.gov/pubmed/27713151 http://dx.doi.org/10.18632/oncotarget.12428 |
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author | Kashyap, Trinayan Argueta, Christian Aboukameel, Amro Unger, Thaddeus John Klebanov, Boris Mohammad, Ramzi M. Muqbil, Irfana Azmi, Asfar S. Drolen, Claire Senapedis, William Lee, Margaret Kauffman, Michael Shacham, Sharon Landesman, Yosef |
author_facet | Kashyap, Trinayan Argueta, Christian Aboukameel, Amro Unger, Thaddeus John Klebanov, Boris Mohammad, Ramzi M. Muqbil, Irfana Azmi, Asfar S. Drolen, Claire Senapedis, William Lee, Margaret Kauffman, Michael Shacham, Sharon Landesman, Yosef |
author_sort | Kashyap, Trinayan |
collection | PubMed |
description | The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent. |
format | Online Article Text |
id | pubmed-5346685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53466852017-03-30 Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death Kashyap, Trinayan Argueta, Christian Aboukameel, Amro Unger, Thaddeus John Klebanov, Boris Mohammad, Ramzi M. Muqbil, Irfana Azmi, Asfar S. Drolen, Claire Senapedis, William Lee, Margaret Kauffman, Michael Shacham, Sharon Landesman, Yosef Oncotarget Research Paper The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent. Impact Journals LLC 2016-10-04 /pmc/articles/PMC5346685/ /pubmed/27713151 http://dx.doi.org/10.18632/oncotarget.12428 Text en Copyright: © 2016 Kashyap et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Kashyap, Trinayan Argueta, Christian Aboukameel, Amro Unger, Thaddeus John Klebanov, Boris Mohammad, Ramzi M. Muqbil, Irfana Azmi, Asfar S. Drolen, Claire Senapedis, William Lee, Margaret Kauffman, Michael Shacham, Sharon Landesman, Yosef Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title | Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title_full | Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title_fullStr | Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title_full_unstemmed | Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title_short | Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
title_sort | selinexor, a selective inhibitor of nuclear export (sine) compound, acts through nf-κb deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346685/ https://www.ncbi.nlm.nih.gov/pubmed/27713151 http://dx.doi.org/10.18632/oncotarget.12428 |
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