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

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dc.contributor.authorPerera, Yasser
dc.contributor.authorMelão, Alice
dc.contributor.authorRamón, Ailyn C.
dc.contributor.authorVázquez, Dania
dc.contributor.authorRibeiro, Daniel
dc.contributor.authorPerea, Silvio E.
dc.contributor.authorBarata, João T.
dc.date.accessioned2022-01-21T11:50:25Z
dc.date.available2022-01-21T11:50:25Z
dc.date.issued2020
dc.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/).pt_PT
dc.description.abstractDespite 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancers (Basel). 2020 May 27;12(6):1377pt_PT
dc.identifier.doi10.3390/cancers12061377pt_PT
dc.identifier.eissn2072-6694
dc.identifier.urihttp://hdl.handle.net/10451/50908
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationIL-7/IL-7R signaling networks in health and malignancy
dc.relation.publisherversionhttps://www.mdpi.com/journal/cancerspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCIGB-300pt_PT
dc.subjectCasein kinase 2 (CK2)pt_PT
dc.subjectIL-7 receptor (IL-7R)pt_PT
dc.subjectIL-7-mediated signalingpt_PT
dc.subjectSignaling therapiespt_PT
dc.subjectStromal supportpt_PT
dc.subjectT-cell acute lymphoblastic leukemia (T-ALL)pt_PT
dc.subjectConflict of interest statementpt_PT
dc.titleClinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal supportpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumber648455
oaire.awardNumberFAPESP/20015/2014
oaire.awardNumberPTDC/MEC-HEM/31588/2017
oaire.awardTitleIL-7/IL-7R signaling networks in health and malignancy
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/648455/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/FAPESP%2F20015%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FMEC-HEM%2F31588%2F2017/PT
oaire.citation.issue6pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume12pt_PT
oaire.fundingStreamH2020
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
person.familyNameMelão
person.familyNameSilva Ribeiro
person.familyNameBarata
person.givenNameAlice
person.givenNameDaniel Filipe
person.givenNameJoão
person.identifier.ciencia-id5B17-5400-736D
person.identifier.ciencia-id7016-104B-7CE8
person.identifier.orcid0000-0001-5629-7796
person.identifier.orcid0000-0003-3660-9646
person.identifier.orcid0000-0002-4826-8976
person.identifier.ridD-9181-2015
person.identifier.scopus-author-id37038033200
person.identifier.scopus-author-id7006937224
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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