Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
| Autor: | Yiliam Cruz, George V. Pérez, Katharina Zettl, Yassel Ramos, Ailyn C. Ramón, Mauro Rosales, Yasser Perera, Vladimir Besada, Luis Javier González, Evelin Caballero, Silvio E. Perea, Arielis Rodríguez-Ulloa, Daylen Aguilar, Ke Yang, Dania Marcia Vazquez-Blomquist, Jacek R. Wiśniewski |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
NPM1 QH301-705.5 Chronic lymphocytic leukemia medicine.medical_treatment media_common.quotation_subject Medicine (miscellaneous) Peptide acute myeloid leukemia General Biochemistry Genetics and Molecular Biology Article Targeted therapy 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases CIGB-300 medicine Biology (General) Internalization media_common chemistry.chemical_classification Nucleophosmin Phosphoproteomics phosphoproteomics Myeloid leukemia medicine.disease 030104 developmental biology chemistry Cell culture 030220 oncology & carcinogenesis protein kinase CK2 Cancer research Phosphorylation Casein kinase 2 |
| Zdroj: | Biomedicines Biomedicines, Vol 9, Iss 766, p 766 (2021) Volume 9 Issue 7 |
| DOI: | 10.1101/2021.05.19.444866 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|