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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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.
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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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