Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/107532
DC Field | Value | Language |
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dc.contributor.author | Bessa, Cláudia | - |
dc.contributor.author | Soares, Joana | - |
dc.contributor.author | Raimundo, Liliana | - |
dc.contributor.author | Loureiro, Joana B. | - |
dc.contributor.author | Gomes, Célia | - |
dc.contributor.author | Reis, Flávio | - |
dc.contributor.author | Soares, Miguel L. | - |
dc.contributor.author | Santos, Daniel | - |
dc.contributor.author | Dureja, Chetna | - |
dc.contributor.author | Chaudhuri, Saumya R. | - |
dc.contributor.author | Lopez-Haber, Cynthia | - |
dc.contributor.author | Kazanietz, Marcelo G. | - |
dc.contributor.author | Gonçalves, Jorge | - |
dc.contributor.author | Simões, Maria F. | - |
dc.contributor.author | Rijo, Patrícia | - |
dc.contributor.author | Saraiva, Lucília | - |
dc.date.accessioned | 2023-07-19T08:40:32Z | - |
dc.date.available | 2023-07-19T08:40:32Z | - |
dc.date.issued | 2018-01-18 | - |
dc.identifier.issn | 2041-4889 | pt |
dc.identifier.uri | https://hdl.handle.net/10316/107532 | - |
dc.description.abstract | Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCδ but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCδ-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCδ-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases. | pt |
dc.language.iso | eng | pt |
dc.publisher | Springer Nature | pt |
dc.relation | FEDER funds POCI/01/0145/FEDER/007728, FCOMP-01-0124-FEDER-028417 and POCI-01-0145-FEDER-007440, through Programa Operacional Factores de Competitividade—COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/ 04378/2013, UID/NEU/04539/2013, UID/DTP/04567/2016, and the project (3599-PPCDT) PTDC/DTP-FTO/1981/2014—POCI-01-0145-FEDER-016581, as well as Centro 2020 Regional Operational Programmes (CENTRO-01-0145- FEDER-000012: HealthyAging2020). FCT fellowships: SFRH/BD/87109/2012 (C. Bessa), SFRH/BD/117949/2016 (L. Raimundo), and SFRH/BD/128673/2017 (J. B. Loureiro). | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt |
dc.subject.mesh | Colonic Neoplasms | pt |
dc.subject.mesh | Humans | pt |
dc.subject.mesh | Protein Kinase C-delta | pt |
dc.title | Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy | pt |
dc.type | article | - |
degois.publication.firstPage | 23 | pt |
degois.publication.issue | 2 | pt |
degois.publication.title | Cell Death and Disease | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1038/s41419-017-0154-9 | pt |
degois.publication.volume | 9 | pt |
dc.date.embargo | 2018-01-18 | * |
uc.date.periodoEmbargo | 0 | pt |
item.grantfulltext | open | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | en | - |
item.openairetype | article | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | Com Texto completo | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.orcid | 0000-0002-7497-4129 | - |
crisitem.author.orcid | 0000-0003-3401-9554 | - |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais I&D IBILI - Artigos em Revistas Internacionais |
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File | Description | Size | Format | |
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Discovery-of-a-smallmolecule-protein-kinase-Cselective-activator-with-promising-application-in-colon-cancer-therapy-articleCell-Death-and-Disease.pdf | 8.76 MB | Adobe PDF | View/Open |
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