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https://hdl.handle.net/10216/126482
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DC Field | Value | Language |
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dc.creator | Bessa, C | - |
dc.creator | Soares, J | - |
dc.creator | Raimundo, L | - |
dc.creator | Loureiro, J | - |
dc.creator | Gomes, C | - |
dc.creator | Reis, F | - |
dc.creator | Soares, ML | - |
dc.creator | Santos, D | - |
dc.creator | Dureja, C | - |
dc.creator | Chaudhuri, S | - |
dc.creator | Lopez-Haber, C | - |
dc.creator | Kazanietz, M | - |
dc.creator | Gonçalves, J | - |
dc.creator | Simões, M | - |
dc.creator | Rijo, P | - |
dc.creator | Saraiva, L | - |
dc.date.accessioned | 2020-03-02T10:34:05Z | - |
dc.date.available | 2020-03-02T10:34:05Z | - |
dc.date.issued | 2018 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | https://hdl.handle.net/10216/126482 | - |
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 PKCd-selective activator, the 7a-acetoxy-6ß-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCd-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCd-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCd but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCd-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 PKCd-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. | - |
dc.description.sponsorship | We thank European Union (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). | - |
dc.language.iso | eng | - |
dc.publisher | Nature | - |
dc.relation | info:eu-repo/grantAgreement/FCT/5876/147358/PT | - |
dc.relation | info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F87109%2F2012/PT | - |
dc.relation.ispartof | Cell Death and Disease, vol.9(2):23 | - |
dc.rights | openAccess | - |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | - |
dc.subject.mesh | Colonic Neoplasms | - |
dc.subject.mesh | Humans | - |
dc.subject.mesh | Protein Kinase C-delta | - |
dc.title | Discovery of a small-molecule protein kinase Cd-selective activator with promising application in colon cancer therapy | - |
dc.type | Artigo em Revista Científica Internacional | - |
dc.contributor.uporto | Instituto de Investigação e Inovação em Saúde | - |
dc.identifier.doi | 10.1038/s41419-017-0154-9 | - |
dc.relation.publisherversion | https://www.nature.com/articles/s41419-017-0154-9 | - |
Appears in Collections: | I3S - Artigo em Revista Científica Internacional |
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File | Description | Size | Format | |
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10.1038-s41419-017-0154-9.pdf | 8.76 MB | Adobe PDF | View/Open |
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