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Differential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal cancer cells

2025-04Artigo científico Acesso aberto
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dc.contributor.authorMartins, Flávia
dc.contributor.authorMachado, Ana L.
dc.contributor.authorCarvalho, Joana
dc.contributor.authorAlmeida, Catarina R.
dc.contributor.authorBeck, Hans C.
dc.contributor.authorCarvalho, Ana S.
dc.contributor.authorBackman, Vadim
dc.contributor.authorMatthiesen, Rune
dc.contributor.authorMatthiesen, Rune
dc.contributor.authorVelho, Sérgia
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.pblNature Publishing Group
dc.date.accessioned2025-05-07T21:35:28Z
dc.date.available2025-05-07T21:35:28Z
dc.date.issued2025-04
dc.descriptionFunding Information: The work was funded by internal grants (MSI and Cancer Challenge 2022) provided by the Institute for Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and by national funds through FCT in the scope of the project 2022.05346.PTDC (https://doi.org/10.54499/2022.05346.PTDC). This article is also a result of the projects (iNOVA4Health\u2013UIDB/04462/2020 and UIDP/04462/2020, and by the Associated Laboratory LS4FUTURE (LA/P/0087/2020), two programs financially supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia / Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior. FM is a Ph.D. student in the Doctoral Program in Biomedicine at the Faculty of Medicine of the University of Porto, and she is funded through a Ph.D. fellowship (SFRH/BD/143669/2019) awarded by the Portuguese Foundation for Science and Technology (FCT). ALM is a Ph.D. student in the Doctoral Program in Biomedicine from the Faculty of Medicine of the University of Porto, and she is funded through a Ph.D. fellowship (2020.08932.BD) awarded by the FCT. JC is hired by IPATIMUP under norma transit\u00F3ria do DL n.\u00B0 57/2016 alterada pela lei n.\u00B0 57/2017 (https://doi.org/10.54499/DL57/2016/CP1363/CT0012). CA was financially supported by national funds (OE), through Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT)/MCTES, within the scope of iBiMED\u2014Institute of Biomedicine (https://doi.org/10.54499/UIDP/04501/2020). ASC is supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (https://doi.org/10.54499/DL57/2016/CP1457/CT0013). VB was supported by NIH grants R01CA228272, R02CA225002,\u00A0U54CA268084, and U54CA261694, NSF grant EFMA1830961, the Center for Physical Genomics and Engineering at Northwestern University, and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. RM is supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (CEEC position, https://doi.org/10.54499/CEECIND/03906/2017/CP1421/CT0004). SV is supported by FCT (https://doi.org/10.54499/2021.01550.CEECIND/CP1663/CT0012). Funding Information: The work was funded by internal grants (MSI and Cancer Challenge 2022) provided by the Institute for Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and by national funds through FCT in the scope of the project 2022.05346.PTDC ( https://doi.org/10.54499/2022.05346.PTDC ). This article is also a result of the projects (iNOVA4Health\u2013UIDB/04462/2020 and UIDP/04462/2020, and by the Associated Laboratory LS4FUTURE (LA/P/0087/2020), two programs financially supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia / Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior. FM is a Ph.D. student in the Doctoral Program in Biomedicine at the Faculty of Medicine of the University of Porto, and she is funded through a Ph.D. fellowship (SFRH/BD/143669/2019) awarded by the Portuguese Foundation for Science and Technology (FCT). ALM is a Ph.D. student in the Doctoral Program in Biomedicine from the Faculty of Medicine of the University of Porto, and she is funded through a Ph.D. fellowship (2020.08932.BD) awarded by the FCT. JC is hired by IPATIMUP under norma transit\u00F3ria do DL n.\u00B0 57/2016 alterada pela lei n.\u00B0 57/2017 ( https://doi.org/10.54499/DL57/2016/CP1363/CT0012 ). CA was financially supported by national funds (OE), through Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT)/MCTES, within the scope of iBiMED\u2014Institute of Biomedicine ( https://doi.org/10.54499/UIDP/04501/2020 ). ASC is supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia ( https://doi.org/10.54499/DL57/2016/CP1457/CT0013 ). VB was supported by NIH grants R01CA228272, R02CA225002, U54CA268084, and U54CA261694, NSF grant EFMA1830961, the Center for Physical Genomics and Engineering at Northwestern University, and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. RM is supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (CEEC position, https://doi.org/10.54499/CEECIND/03906/2017/CP1421/CT0004 ). SV is supported by FCT ( https://doi.org/10.54499/2021.01550.CEECIND/CP1663/CT0012 ). Funding Information: The authors acknowledge the support of Catarina Meireles and Emilia Cardoso from the Translational Cytometry unit (TraCy) i3S Scientific Platform. We acknowledge the COST Action CA20113 \u201CPROTEOCURE\u201D supported by COST (European Cooperation in Science and Technology). Publisher Copyright: © The Author(s) 2025.
dc.description.abstractDespite the development of mutant-selective KRAS inhibitors, colorectal cancer (CRC) responses remain limited, with stable disease and rapid recurrence being common outcomes. The molecular mechanisms enabling CRC cells to tolerate KRAS inhibition and ultimately develop resistance remain poorly understood. Here, we investigated early transcriptional and proteomic responses to KRAS silencing in 3D CRC cell line spheroid models, aiming to identify pathways associated with sensitivity or resistance to KRAS blockade. Cell lines were stratified into KRAS silencing-sensitive (HCT116 and SW480) and -resistant (LS174T and SW837) groups based on spheroid growth, cell cycle progression, and apoptosis induction. Transcriptional profiling revealed the unfolded protein response (UPR) and WNT/β-catenin signaling as pathways specifically upregulated in KRAS silencing-sensitive cells and downregulated in resistant cells. Proteomic analysis of membrane-enriched fractions further supported UPR deregulation, showing a pronounced downregulation of translation-related proteins in sensitive cells. Functional assays validated that the sensitive cell line HCT116 exhibits reduced protein aggregation and lower translational capacity upon KRAS knockdown, consistent with UPR activation. Pharmacological inhibition of IRE1α-mediated UPR signaling did not revert KRAS silencing-induced cell cycle arrest or apoptosis in this cell line. Collectively, our results highlight the UPR activation as an early adaptive response of KRAS-dependent CRC cells to KRAS silencing.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent8378194
dc.identifier.doi10.1038/s41598-025-94549-2
dc.identifier.issn2045-2322
dc.identifier.otherPURE: 115798878
dc.identifier.otherPURE UUID: 8c38c8a4-12e2-4ffa-a389-c748f3daed07
dc.identifier.otherScopus: 105003450752
dc.identifier.urihttp://hdl.handle.net/10362/182833
dc.identifier.urlhttps://www.scopus.com/pages/publications/105003450752
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral
dc.subjectSDG 3 - Good Health and Well-being
dc.titleDifferential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal cancer cellsen
dc.typejournal article
degois.publication.issue1
degois.publication.titleScientific Reports
degois.publication.volume15
dspace.entity.typePublication
person.familyNameMatthiesen
person.givenNameRune
person.identifier1319342
person.identifier.ciencia-idBB1A-A606-EE77
person.identifier.orcid0000-0002-6353-2616
person.identifier.scopus-author-id9741897800
rcaap.rightsopenAccess
relation.isAuthorOfPublication67181d3c-b83e-4151-9a74-0ea14aeb7f05
relation.isAuthorOfPublication.latestForDiscovery67181d3c-b83e-4151-9a74-0ea14aeb7f05

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