NF-kappa B signaling mediates acquired resistance after PARP inhibition

PARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We establ...

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Detalles Bibliográficos
Autores: Nakagawa, Yuko, Sedukhina, Anna S., Okamoto, Naoki, Nagasawa, Satoi, Suzuki, Nao, Ohta, Tomohiko, Hattori, Hiroyoshi, Roche-Molina, Marta, Narvaez, Ana J., Jeyasekharan, Anand D., Bernal, Juan Antonio, Sato, Ko
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/5512
Acceso en línea:http://hdl.handle.net/20.500.12105/5512
Access Level:acceso abierto
Palabra clave:MULTIPLE-MYELOMA CELLS
POLY(ADP-RIBOSE) POLYMERASE
THERAPY
CANCER
OLAPARIB
ACTIVATION
EXPRESSION
APOPTOSIS
PATHWAY
TARGET
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/5512
network_acronym_str ES
network_name_str España
repository_id_str
spelling NF-kappa B signaling mediates acquired resistance after PARP inhibitionNakagawa, YukoSedukhina, Anna S.Okamoto, NaokiNagasawa, SatoiSuzuki, NaoOhta, TomohikoHattori, HiroyoshiRoche-Molina, MartaNarvaez, Ana J.Jeyasekharan, Anand D.Bernal, Juan AntonioSato, KoMULTIPLE-MYELOMA CELLSPOLY(ADP-RIBOSE) POLYMERASETHERAPYCANCEROLAPARIBACTIVATIONEXPRESSIONAPOPTOSISPATHWAYTARGETPARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We established cell lines that are resistant to PARP inhibitor by continuous treatment with the drug, and then used RNA sequencing to compare gene expression. Pathway analysis on the RNA sequencing data indicates that NF-kappa B signaling is preferentially up-regulated in PARP inhibitor-resistant cells, and that knockdown of core components in NF-kappa B signaling reverses the sensitivity to PARP inhibitor in resistant cells. Of therapeutic relevance, we show that PARP inhibitor-resistant cells are sensitive to an NF-kappa B inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-kappa B are sensitive to bortezomib, a proteasome inhibitor that is currently used in the clinic. We also show that treatment with bortezomib results in cell death in the PARP inhibitor-resistant cells, but not in parental cells. Therefore we propose that up-regulation of NF-kappa B signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-kappa B inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors.Impact JournalsSt. Marianna University20172017-12-0120152015-01-0120152015-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/20.500.12105/5512reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/55122026-06-12T12:43:37Z
dc.title.none.fl_str_mv NF-kappa B signaling mediates acquired resistance after PARP inhibition
title NF-kappa B signaling mediates acquired resistance after PARP inhibition
spellingShingle NF-kappa B signaling mediates acquired resistance after PARP inhibition
Nakagawa, Yuko
MULTIPLE-MYELOMA CELLS
POLY(ADP-RIBOSE) POLYMERASE
THERAPY
CANCER
OLAPARIB
ACTIVATION
EXPRESSION
APOPTOSIS
PATHWAY
TARGET
title_short NF-kappa B signaling mediates acquired resistance after PARP inhibition
title_full NF-kappa B signaling mediates acquired resistance after PARP inhibition
title_fullStr NF-kappa B signaling mediates acquired resistance after PARP inhibition
title_full_unstemmed NF-kappa B signaling mediates acquired resistance after PARP inhibition
title_sort NF-kappa B signaling mediates acquired resistance after PARP inhibition
dc.creator.none.fl_str_mv Nakagawa, Yuko
Sedukhina, Anna S.
Okamoto, Naoki
Nagasawa, Satoi
Suzuki, Nao
Ohta, Tomohiko
Hattori, Hiroyoshi
Roche-Molina, Marta
Narvaez, Ana J.
Jeyasekharan, Anand D.
Bernal, Juan Antonio
Sato, Ko
author Nakagawa, Yuko
author_facet Nakagawa, Yuko
Sedukhina, Anna S.
Okamoto, Naoki
Nagasawa, Satoi
Suzuki, Nao
Ohta, Tomohiko
Hattori, Hiroyoshi
Roche-Molina, Marta
Narvaez, Ana J.
Jeyasekharan, Anand D.
Bernal, Juan Antonio
Sato, Ko
author_role author
author2 Sedukhina, Anna S.
Okamoto, Naoki
Nagasawa, Satoi
Suzuki, Nao
Ohta, Tomohiko
Hattori, Hiroyoshi
Roche-Molina, Marta
Narvaez, Ana J.
Jeyasekharan, Anand D.
Bernal, Juan Antonio
Sato, Ko
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv St. Marianna University
dc.subject.none.fl_str_mv MULTIPLE-MYELOMA CELLS
POLY(ADP-RIBOSE) POLYMERASE
THERAPY
CANCER
OLAPARIB
ACTIVATION
EXPRESSION
APOPTOSIS
PATHWAY
TARGET
topic MULTIPLE-MYELOMA CELLS
POLY(ADP-RIBOSE) POLYMERASE
THERAPY
CANCER
OLAPARIB
ACTIVATION
EXPRESSION
APOPTOSIS
PATHWAY
TARGET
description PARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We established cell lines that are resistant to PARP inhibitor by continuous treatment with the drug, and then used RNA sequencing to compare gene expression. Pathway analysis on the RNA sequencing data indicates that NF-kappa B signaling is preferentially up-regulated in PARP inhibitor-resistant cells, and that knockdown of core components in NF-kappa B signaling reverses the sensitivity to PARP inhibitor in resistant cells. Of therapeutic relevance, we show that PARP inhibitor-resistant cells are sensitive to an NF-kappa B inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-kappa B are sensitive to bortezomib, a proteasome inhibitor that is currently used in the clinic. We also show that treatment with bortezomib results in cell death in the PARP inhibitor-resistant cells, but not in parental cells. Therefore we propose that up-regulation of NF-kappa B signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-kappa B inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015-01-01
2015
2015-01-01
2017
2017-12-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/5512
url http://hdl.handle.net/20.500.12105/5512
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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