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Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export

Chromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin‐1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as...

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Autores principales: Jimenez, Lucia, Mayoral‐Varo, Victor, Amenábar, Carlos, Ortega, Judit, Sequeira, João G. N., Machuqueiro, Miguel, Mourato, Cristiana, Silvestri, Romano, Angeli, Andrea, Carta, Fabrizio, Supuran, Claudiu T., Megías, Diego, Ferreira, Bibiana I., Link, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons A/S 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099545/
https://www.ncbi.nlm.nih.gov/pubmed/36353954
http://dx.doi.org/10.1111/tra.12872
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author Jimenez, Lucia
Mayoral‐Varo, Victor
Amenábar, Carlos
Ortega, Judit
Sequeira, João G. N.
Machuqueiro, Miguel
Mourato, Cristiana
Silvestri, Romano
Angeli, Andrea
Carta, Fabrizio
Supuran, Claudiu T.
Megías, Diego
Ferreira, Bibiana I.
Link, Wolfgang
author_facet Jimenez, Lucia
Mayoral‐Varo, Victor
Amenábar, Carlos
Ortega, Judit
Sequeira, João G. N.
Machuqueiro, Miguel
Mourato, Cristiana
Silvestri, Romano
Angeli, Andrea
Carta, Fabrizio
Supuran, Claudiu T.
Megías, Diego
Ferreira, Bibiana I.
Link, Wolfgang
author_sort Jimenez, Lucia
collection PubMed
description Chromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin‐1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose‐limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein‐labeled HIV‐1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1‐mediated export, can be followed by co‐culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110α, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110α partially relies on CRM1‐dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1‐independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.
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spelling pubmed-100995452023-04-14 Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export Jimenez, Lucia Mayoral‐Varo, Victor Amenábar, Carlos Ortega, Judit Sequeira, João G. N. Machuqueiro, Miguel Mourato, Cristiana Silvestri, Romano Angeli, Andrea Carta, Fabrizio Supuran, Claudiu T. Megías, Diego Ferreira, Bibiana I. Link, Wolfgang Traffic Research Articles Chromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin‐1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose‐limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein‐labeled HIV‐1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1‐mediated export, can be followed by co‐culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110α, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110α partially relies on CRM1‐dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1‐independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor. John Wiley & Sons A/S 2022-11-29 2022-12 /pmc/articles/PMC10099545/ /pubmed/36353954 http://dx.doi.org/10.1111/tra.12872 Text en © 2022 The Authors. Traffic published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Jimenez, Lucia
Mayoral‐Varo, Victor
Amenábar, Carlos
Ortega, Judit
Sequeira, João G. N.
Machuqueiro, Miguel
Mourato, Cristiana
Silvestri, Romano
Angeli, Andrea
Carta, Fabrizio
Supuran, Claudiu T.
Megías, Diego
Ferreira, Bibiana I.
Link, Wolfgang
Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title_full Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title_fullStr Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title_full_unstemmed Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title_short Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
title_sort multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of crm1‐mediated nuclear export
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099545/
https://www.ncbi.nlm.nih.gov/pubmed/36353954
http://dx.doi.org/10.1111/tra.12872
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