Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma

9 pags, 3 figs

Bibliographic Details
Authors: Santofimia-Castaño, Patricia, Xia, Yi, Peng, Ling, Velázquez-Campoy, Adrián, Abian, Olga, Lan, Wenjun, Lomberk, Gwen, Urrutia, Raul, Rizzuti, Bruno, Soubeyran, Philippe, Neira, José L., Iovanna, Juan Lucio
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/259297
Online Access:http://hdl.handle.net/10261/259297
https://api.elsevier.com/content/abstract/scopus_id/85082729502
Access Level:Open access
Keyword:NUPR1
Drug design
Intrinsically disordered protein
Molecular dynamics
Pancreatic ductal adenocarcinoma
Spectroscopy
Stress response
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spelling Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinomaSantofimia-Castaño, PatriciaXia, YiPeng, LingVelázquez-Campoy, AdriánAbian, OlgaLan, WenjunLomberk, GwenUrrutia, RaulRizzuti, BrunoSoubeyran, PhilippeNeira, José L.Iovanna, Juan LucioNUPR1Drug designIntrinsically disordered proteinMolecular dynamicsPancreatic ductal adenocarcinomaSpectroscopyStress response9 pags, 3 figsCancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the Nupr1 gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.This work in the authors' laboratories was supported by La Ligue Contre le Cancer, INCa, Fondation de France, and INSERM (to JI); Fondation ARC (to PS); the Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017 to OA); the Fondo de Investigaciones Sanitarias (PI15/00663 and PI18/00343 to OA); the Spanish Ministry of Economy and Competitiveness (BFU2016-78232-P to AVC, RTI2018 097991-BIO to JLN); the Diputacion General de Aragon (Protein Targets Group B89 to AVC, and Digestive Pathology Group B01 to OA); the Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd); the Fundacion Alfonso Martin-Escudero and Fondation de France (to PSC); the China Scholarship Council (to WL and CH); Programme XU GUANGQI and CAI YUANPEI (to YX and JI); and the National Natural Science Foundation of China (81502920 to YX).Peer reviewedMultidisciplinary Digital Publishing InstituteLigue Nationale contre le Cancer (France)Institut National du Cancer (France)Fondation de FranceInstitut National de la Santé et de la Recherche Médicale (France)Fondation ARC pour la Recherche sur le CancerInstituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)Diputación General de AragónCentro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)Fundación Alfonso Martín EscuderoNational Natural Science Foundation of ChinaChina Scholarship CouncilConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/259297https://api.elsevier.com/content/abstract/scopus_id/85082729502reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//BFU2016-78232-Pinfo:eu-repo/grantAgreement/MINECO//RTI2018-097991-BIOCellshttp://dx.doi.org/10.3390/cells8111453Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2592972026-05-22T06:33:51Z
dc.title.none.fl_str_mv Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
title Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
spellingShingle Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
Santofimia-Castaño, Patricia
NUPR1
Drug design
Intrinsically disordered protein
Molecular dynamics
Pancreatic ductal adenocarcinoma
Spectroscopy
Stress response
title_short Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
title_full Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
title_fullStr Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
title_full_unstemmed Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
title_sort Targeting the stress-induced protein NUPR1 to treat pancreatic adenocarcinoma
dc.creator.none.fl_str_mv Santofimia-Castaño, Patricia
Xia, Yi
Peng, Ling
Velázquez-Campoy, Adrián
Abian, Olga
Lan, Wenjun
Lomberk, Gwen
Urrutia, Raul
Rizzuti, Bruno
Soubeyran, Philippe
Neira, José L.
Iovanna, Juan Lucio
author Santofimia-Castaño, Patricia
author_facet Santofimia-Castaño, Patricia
Xia, Yi
Peng, Ling
Velázquez-Campoy, Adrián
Abian, Olga
Lan, Wenjun
Lomberk, Gwen
Urrutia, Raul
Rizzuti, Bruno
Soubeyran, Philippe
Neira, José L.
Iovanna, Juan Lucio
author_role author
author2 Xia, Yi
Peng, Ling
Velázquez-Campoy, Adrián
Abian, Olga
Lan, Wenjun
Lomberk, Gwen
Urrutia, Raul
Rizzuti, Bruno
Soubeyran, Philippe
Neira, José L.
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ligue Nationale contre le Cancer (France)
Institut National du Cancer (France)
Fondation de France
Institut National de la Santé et de la Recherche Médicale (France)
Fondation ARC pour la Recherche sur le Cancer
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Diputación General de Aragón
Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)
Fundación Alfonso Martín Escudero
National Natural Science Foundation of China
China Scholarship Council
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv NUPR1
Drug design
Intrinsically disordered protein
Molecular dynamics
Pancreatic ductal adenocarcinoma
Spectroscopy
Stress response
topic NUPR1
Drug design
Intrinsically disordered protein
Molecular dynamics
Pancreatic ductal adenocarcinoma
Spectroscopy
Stress response
description 9 pags, 3 figs
publishDate 2019
dc.date.none.fl_str_mv 2019
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/259297
https://api.elsevier.com/content/abstract/scopus_id/85082729502
url http://hdl.handle.net/10261/259297
https://api.elsevier.com/content/abstract/scopus_id/85082729502
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//BFU2016-78232-P
info:eu-repo/grantAgreement/MINECO//RTI2018-097991-BIO
Cells
http://dx.doi.org/10.3390/cells8111453
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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