Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support

Detalhes bibliográficos
Autor(a) principal: Perera, Yasser
Data de Publicação: 2020
Outros Autores: Melão, Alice, Ramón, Ailyn C., Vázquez, Dania, Ribeiro, Daniel, Perea, Silvio E., Barata, João T.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/50908
Resumo: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
id RCAP_04e54f9209678e939551de3afdc37598
oai_identifier_str oai:repositorio.ul.pt:10451/50908
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal supportCIGB-300Casein kinase 2 (CK2)IL-7 receptor (IL-7R)IL-7-mediated signalingSignaling therapiesStromal supportT-cell acute lymphoblastic leukemia (T-ALL)Conflict of interest statement© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase / signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.This work was supported by the consolidator grant ERC CoG-648455 from the European Research Council, under the European Union’s Horizon 2020 research and innovation program, and FAPESP/20015/2014 and PTDC/MEC-HEM/31588/2017 grants from Fundação para a Ciência e a Tecnologia (FCT), to JTB.MDPIRepositório da Universidade de LisboaPerera, YasserMelão, AliceRamón, Ailyn C.Vázquez, DaniaRibeiro, DanielPerea, Silvio E.Barata, João T.2022-01-21T11:50:25Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/50908engCancers (Basel). 2020 May 27;12(6):137710.3390/cancers120613772072-6694info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:55:18Zoai:repositorio.ul.pt:10451/50908Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:02:15.589602Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
title Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
spellingShingle Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
Perera, Yasser
CIGB-300
Casein kinase 2 (CK2)
IL-7 receptor (IL-7R)
IL-7-mediated signaling
Signaling therapies
Stromal support
T-cell acute lymphoblastic leukemia (T-ALL)
Conflict of interest statement
title_short Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
title_full Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
title_fullStr Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
title_full_unstemmed Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
title_sort Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support
author Perera, Yasser
author_facet Perera, Yasser
Melão, Alice
Ramón, Ailyn C.
Vázquez, Dania
Ribeiro, Daniel
Perea, Silvio E.
Barata, João T.
author_role author
author2 Melão, Alice
Ramón, Ailyn C.
Vázquez, Dania
Ribeiro, Daniel
Perea, Silvio E.
Barata, João T.
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Perera, Yasser
Melão, Alice
Ramón, Ailyn C.
Vázquez, Dania
Ribeiro, Daniel
Perea, Silvio E.
Barata, João T.
dc.subject.por.fl_str_mv CIGB-300
Casein kinase 2 (CK2)
IL-7 receptor (IL-7R)
IL-7-mediated signaling
Signaling therapies
Stromal support
T-cell acute lymphoblastic leukemia (T-ALL)
Conflict of interest statement
topic CIGB-300
Casein kinase 2 (CK2)
IL-7 receptor (IL-7R)
IL-7-mediated signaling
Signaling therapies
Stromal support
T-cell acute lymphoblastic leukemia (T-ALL)
Conflict of interest statement
description © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-01T00:00:00Z
2022-01-21T11:50:25Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/50908
url http://hdl.handle.net/10451/50908
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cancers (Basel). 2020 May 27;12(6):1377
10.3390/cancers12061377
2072-6694
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799134572478201856

Registros relacionados