Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export
Autor(a) principal: | |
---|---|
Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/19058 |
Resumo: | 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, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha 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. |
id |
RCAP_ecf41472e3e1d82834ab48647b10aaa4 |
---|---|
oai_identifier_str |
oai:sapientia.ualg.pt:10400.1/19058 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear exportAnticancer drugsAntiviral drugsBiosensorsCRM1Nuclear exportOrganoselenium compoundsSelinexorChromosomal 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, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha 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.WileySapientiaJimenez, LuciaMayoral‐Varo, VictorAmenábar, CarlosOrtega, JuditSequeira, João G. N.Machuqueiro, MiguelMourato, CristianaSilvestri, RomanoAngeli, AndreaCarta, FabrizioSupuran, Claudiu T.Megías, DiegoFerreira, BibianaLink, Wolfgang2023-02-11T11:01:33Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/19058eng1398-921910.1111/tra.12872info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:31:28Zoai:sapientia.ualg.pt:10400.1/19058Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:08:44.292987Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
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 |
spellingShingle |
Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export Jimenez, Lucia Anticancer drugs Antiviral drugs Biosensors CRM1 Nuclear export Organoselenium compounds Selinexor |
title_short |
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_sort |
Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export |
author |
Jimenez, Lucia |
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 Link, Wolfgang |
author_role |
author |
author2 |
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 Link, Wolfgang |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
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 Link, Wolfgang |
dc.subject.por.fl_str_mv |
Anticancer drugs Antiviral drugs Biosensors CRM1 Nuclear export Organoselenium compounds Selinexor |
topic |
Anticancer drugs Antiviral drugs Biosensors CRM1 Nuclear export Organoselenium compounds Selinexor |
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, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha 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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022 2022-01-01T00:00:00Z 2023-02-11T11:01:33Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/19058 |
url |
http://hdl.handle.net/10400.1/19058 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1398-9219 10.1111/tra.12872 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Wiley |
publisher.none.fl_str_mv |
Wiley |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799133334266183680 |