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Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300

Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based...

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Autores principales: Rosales, Mauro, Pérez, George V., Ramón, Ailyn C., Cruz, Yiliam, Rodríguez-Ulloa, Arielis, Besada, Vladimir, Ramos, Yassel, Vázquez-Blomquist, Dania, Caballero, Evelin, Aguilar, Daylen, González, Luis J., Zettl, Katharina, Wiśniewski, Jacek R., Yang, Ke, Perera, Yasser, Perea, Silvio E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301452/
https://www.ncbi.nlm.nih.gov/pubmed/34356831
http://dx.doi.org/10.3390/biomedicines9070766
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author Rosales, Mauro
Pérez, George V.
Ramón, Ailyn C.
Cruz, Yiliam
Rodríguez-Ulloa, Arielis
Besada, Vladimir
Ramos, Yassel
Vázquez-Blomquist, Dania
Caballero, Evelin
Aguilar, Daylen
González, Luis J.
Zettl, Katharina
Wiśniewski, Jacek R.
Yang, Ke
Perera, Yasser
Perea, Silvio E.
author_facet Rosales, Mauro
Pérez, George V.
Ramón, Ailyn C.
Cruz, Yiliam
Rodríguez-Ulloa, Arielis
Besada, Vladimir
Ramos, Yassel
Vázquez-Blomquist, Dania
Caballero, Evelin
Aguilar, Daylen
González, Luis J.
Zettl, Katharina
Wiśniewski, Jacek R.
Yang, Ke
Perera, Yasser
Perea, Silvio E.
author_sort Rosales, Mauro
collection PubMed
description Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy.
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spelling pubmed-83014522021-07-24 Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300 Rosales, Mauro Pérez, George V. Ramón, Ailyn C. Cruz, Yiliam Rodríguez-Ulloa, Arielis Besada, Vladimir Ramos, Yassel Vázquez-Blomquist, Dania Caballero, Evelin Aguilar, Daylen González, Luis J. Zettl, Katharina Wiśniewski, Jacek R. Yang, Ke Perera, Yasser Perea, Silvio E. Biomedicines Article Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy. MDPI 2021-07-01 /pmc/articles/PMC8301452/ /pubmed/34356831 http://dx.doi.org/10.3390/biomedicines9070766 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rosales, Mauro
Pérez, George V.
Ramón, Ailyn C.
Cruz, Yiliam
Rodríguez-Ulloa, Arielis
Besada, Vladimir
Ramos, Yassel
Vázquez-Blomquist, Dania
Caballero, Evelin
Aguilar, Daylen
González, Luis J.
Zettl, Katharina
Wiśniewski, Jacek R.
Yang, Ke
Perera, Yasser
Perea, Silvio E.
Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title_full Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title_fullStr Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title_full_unstemmed Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title_short Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
title_sort targeting of protein kinase ck2 in acute myeloid leukemia cells using the clinical-grade synthetic-peptide cigb-300
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301452/
https://www.ncbi.nlm.nih.gov/pubmed/34356831
http://dx.doi.org/10.3390/biomedicines9070766
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