RT Journal Article
SR Electronic
T1 Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.19.444866
DO 10.1101/2021.05.19.444866
A1 Mauro Rosales
A1 George V. Pérez
A1 Ailyn C. Ramón
A1 Yiliam Cruz
A1 Arielis Rodríguez-Ulloa
A1 Vladimir Besada
A1 Yassel Ramos
A1 Dania Vázquez-Blomquist
A1 Evelin Caballero
A1 Daylen Aguilar
A1 Luis J. González
A1 Katharina Zettl
A1 Jacek R. Wiśniewski
A1 Yang Ke
A1 Yasser Perera
A1 Silvio E. Perea
YR 2021
UL http://biorxiv.org/content/early/2021/05/20/2021.05.19.444866.abstract
AB Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), 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.Competing Interest StatementThe authors have declared no competing interest.